Manuscript File 1 Neurobehavioral and neurodevelopmental profiles of a heuristic 1 2 2 genetic model of differential schizophrenia- and addiction-relevant 3 3 features: the RHA vs. RLA rats 4 5 6 4 Alberto Fernández-Teruel 1*, Ignasi Oliveras 1, Toni Cañete 1, Cristóbal Rio-Álamos 7 5 2, Carles Tapias-Espinosa 1, Daniel Sampedro-Viana 1, Ana Sánchez-González 1, 8 6 9 Francesco Sanna 3, Rafael Torrubia 1, Javier González-Maeso 4, Peter Driscoll 5, 10 7 Ignacio Morón 6, Carmen Torres 7*, Susana Aznar 8*, Adolf Tobeña 1*, Maria G. 11 8 Corda 3*, Osvaldo Giorgi 3*. 12 13 14 9 1 Medical Psychology Unit, Department of Psychiatry & Forensic Medicine, Institute 15 10 of Neurosciences, Autonomous University of Barcelona, 08193-Bellaterra, Barcelona, 16 11 17 Spain 18 19 12 2 Department of Psychology, Austral University of Chile, Valdivia, Chile 20 21 13 3 Department of Life and Environmental Sciences (DiSVA), University of Cagliari, 22 14 23 Italy 24 25 15 4 Department of Physiology and Biophysics, Virginia Commonwealth University 26 16 School of Medicine, Richmond, VA, USA. 27 28 17 29 5. Mittelgasse 15, Flawil, Switzerland 30 31 18 6. Department of Psychobiology and Centre of Investigation of Mind, Brain, and 32 19 Behaviour (CIMCYC), University of Granada, Spain. 33 34 20 35 7. Department of Psychology, University of Jaén, 23071, Jaén, Spain 36 37 21 8. Research Laboratory for Stereology and Neuroscience, Bispebjerg Copenhagen 38 22 University Hospital, 2400 Copenhagen, Denmark 39 40 23 41 42 43 24 *Corresponding authors: 44 45 25 46 albert.fernandez.teruel@uab.cat, mctorres@ujaen.es, adolf.tobena@uab.cat, 47 26 susana.aznar.kleijn@regionh.dk, mgcorda@unica.it, giorgi@unica.it 48 49 50 27 51 52 28 Pages: 72 53 29 54 References: 400 55 30 56 Tables: 3 57 31 58 Figures: 2 59 32 Supplementary tables: 2 60 61 62 1 63 64 65 1 ABSTRACT 1 2 3 2 The Roman High- (RHA) and Low-(RLA) avoidance rat lines/strains were generated 4 3 through bidirectional selective breeding for rapid (RHA) vs. extremely poor (RLA) two- 5 6 4 way active avoidance acquisition. Compared with RLAs and other rat strains/stocks, 7 8 5 RHAs are characterized by increased impulsivity, deficits in social behavior, novelty- 9 10 6 induced hyper-locomotion, impaired attentional/cognitive abilities, vulnerability to 11 12 7 psychostimulant sensitization and drug addiction. RHA rats also exhibit decreased 13 14 8 function of the prefrontal cortex (PFC) and hippocampus, increased functional activity of 15 9 the mesolimbic dopamine system and a dramatic deficit of central metabotropic 16 17 10 glutamate-2 (mGlu2) receptors (due to a stop codon mutation at cysteine 407 in Grm2 - 18 19 11 cys407*-), along with increased density of 5-HT2A receptors in the PFC, alterations of 20 21 12 several synaptic markers and increased density of pyramidal “thin” (immature) dendrític 22 23 13 spines in the PFC. These characteristics suggest an immature brain of RHA rats, and are 24 25 14 reminiscent of schizophrenia features like hypofrontality and disruption of the 26 15 27 excitation/inhibition cortical balance. RHA rats represent a promising heuristic model of 28 16 neurodevelopmental schizophrenia-relevant features and comorbidity with drug addiction 29 30 17 vulnerability. 31 32 18 33 34 35 19 Keywords: Roman high- and low-avoidance rats, neurodevelopmental genetic model, 36 20 37 schizophrenia-relevant features, glutamate, GABA, mesocorticolimbic dopaminergic 38 21 pathways, nucleus accumbens, medial prefrontal cortex, hippocampus 39 40 41 22 42 43 44 23 45 46 24 47 48 49 25 50 51 52 26 53 54 27 55 56 57 28 58 59 60 29 61 62 2 63 64 65 1 1. Introduction 1 2 3 2 Schizophrenia is a chronic mental disorder affecting about 1 % of the world population. 4 3 The main manifestations of schizophrenia are classified into ‘positive’ symptoms (e.g. 5 6 4 hallucinations, delusions, thought disorders), ‘negative’ symptoms (e.g. social 7 8 5 withdrawal, apathy) and “cognitive” symptoms (e.g. attentional deficits, impairment of 9 10 6 working memory). Antipsychotic medications are only partially effective: around 30% of 11 12 7 patients are unresponsive to therapy (Sawa and Snyder, 2002; Powell and Miyakawa, 13 14 8 2006; Jones et al., 2011; Kapur, 2003; González-Maeso et al., 2008; Snyder, 2008). 15 16 9 Human genetic studies have revealed the existence of many susceptibility genes for 17 18 10 schizophrenia (reviews by Sawa and Snyder, 2002; Powell and Miyakawa, 2006; 19 20 11 González-Maeso and Sealfon, 2009; Schizophrenia Working Group of the Psychiatric 21 22 12 Genomics Consortium 2014; Flint and Munafo 2014). Interactions between 23 24 13 susceptibility genes and environment are thought to play a prominent role (Powell and 25 14 26 Miyakawa, 2006). Thus, the current view is that schizophrenia is a polygenic 27 15 neurodevelopmental cognitive disorder that cannot be reduced to its psychotic symptoms 28 29 16 and is not just a result of abnormal dopamine or serotonin functioning (Geyer et al., 2012; 30 31 17 Millan et al., 2016; Sawa and Snyder, 2002; Powell and Miyakawa, 2006; Jones et al., 32 33 18 2011; Schizophrenia Working Group of the Psychiatric Genomics Consortium 2014 ). 34 35 19 There is an urgent need to establish newer and heuristic animal models that can take into 36 20 37 account these insights from human studies and contribute both to our knowledge of the 38 21 neurobiology of the disorder and to the development of new drugs/treatments capable of 39 40 22 improving the negative symptoms and cognitive disfunctions of schizophrenia (Del Rio 41 42 23 et al., 2014; Ellenbroek and Karl 2016; Fernando and Robbins 2011; Geyer et al., 2012; 43 44 24 Jones et al., 2011; Powell and Miyakawa, 2006). 45 46 25 47 On the other hand, schizophrenia is associated with a remarkably high prevalence of 48 26 cocaine, amphetamine, alcohol, cannabis, and nicotine use (reviewed by Giorgi et al., 49 50 27 2019). Experimental evidence accumulated in recent years supports the view that the 51 52 28 pathologic substrate of schizophrenia may contribute to the susceptibility to addiction by 53 54 29 facilitating the functional activity of the neural circuitry that mediates positive 55 56 30 reinforcement (Chambers et al., 2001). Hence, the hypothesis implies that both the 57 31 58 schizophrenia syndrome and vulnerability to addiction are primary disease symptoms, 59 32 each directly caused by common neuropathological substrates, of which 60 61 62 3 63 64 65 1 mesocorticolimbic dopamine (DA) seems to be a crucial component (e.g. Chambers et 1 2 2 al., 2001; Giorgi et al., 2019). 3 4 3 The main aim of the present article is to review, under a neurodevopmental focus, the 5 6 4 most relevant neurobehavioral and molecular features of a rat model based on 7 8 5 psychogenetic selection and breeding that presents divergent strain-dependent 9 10 6 schizophrenia-relevant and addiction-related features/phenotypes: the Roman high- 11 12 7 (RHA) and low-avoidance (RLA) rat lines/strains. 13 14 8 15 16 17 9 1. The Roman rats: main behavioral and psychopharmacological phenotypes 18 19 20 10 The Roman rat lines were established in Rome in the early 1960s through bidirectional 21 22 11 selection and outbreeding of Wistar rats showing very high (RHA) vs. extremely low 23 12 (RLA) rates of acquisition of the two-way active avoidance response (Bignami, 1965; 24 25 13 26 Bignami and Bovet 1965). After the fifth generation of selection the two lines were moved 27 14 to Birmingham, UK (Broadhurst and Bignami 1965), where selective breeding continued 28 29 15 (e.g. Wilcock and Fulker 1973; Wilcock et al., 1981). 30 31 16 Two outbred swiss sublines (named RHA/Verh and RLA/Verh), derived from the original 32 33 17 lines from Birmingham, were established in Zurich, Switzerland in 1972 (Bättig and 34 18 Schlatter, 1978; Bättig et al., 1976; Driscoll, 1976; Driscoll and Bättig, 1979; Driscoll 35 36 19 37 and Käsermann, 1977; Driscoll et al., 1979, 1980; Duetsch and Bättig, 1977). Other 38 20 outbred sublines, from the Zurich stock, were established in Cagliari, Italy (Giorgi et al., 39 40 21 1994, 1997, 2003a-b, 2005a-b, 2007; Sabariego et al., 2019), and Geneva, Switzerland 41 42 22 (Steimer et al., 1997a,b). In addition, inbred Roman (RHA-I and RLA-I) strains, 43 23 44 generated through brother/sister mating of the respective Swiss/Verh sublines, were 45 24 46 established in Barcelona in 1995 (Driscoll et al., 1998, 2009; Escorihuela et al., 1997, 47 25 48 1999). Over 260 international articles have been published on the Roman rats (or using 49 26 50 them as part of broader studies) during the fifty-five years since the original Roman rat 51 27 52 lines were generated (150 of these have been published between 1995 and 2020). 53 28 54 Supplementary Table S1 summarizes the main findings and milestones achieved by the 55 29 different laboratories that have conducted research in the past with the Roman rats as well 56 57 30 as from those groups that continue to conduct and publish neurobiological research using 58 59 31 the Roman rat lines/strains as subjects. 60 61 62 4 63 64 65 1 To sum up, compared with RHAs and various other rat strains/stocks, RLA rats display 1 2 2 enhanced anxiety, fear and stress hormone responses in the face of unconditioned or 3 3 conditioned threatening situations, as well as enhanced signs of frustration in reward 4 5 4 devaluation tasks (reviewed in Giorgi et al., 2019; Papini et al., 2015; Steimer and 6 7 5 Driscoll 2003; see Table S1 and references therein). Consistently, the anxious profile of 8 9 6 RLA rats in different tests/tasks is attenuated or reversed by the administration of 10 11 7 anxiolytic drugs and increased by known anxiogenic drugs (see a summary of these 12 13 8 studies in Table S2). 14 15 9 On their side, compared with RLAs and other rat strains/stocks, RHA rats exhibit a large 16 17 10 number of schizophrenia- and addiction-related traits, such as (see review by Giorgi et 18 19 11 al., 2019): 20 21 22 12 (i)- enhanced novelty-induced locomotor activity (Table 1); 23 24 13 25 (ii)- increased impulsivity and novelty seeking (these are correlated traits that are related 26 14 27 to both schizophrenia and addiction vulnerability in humans; Ahn et al., 2011; Brown et 28 15 al., 2018; Ho et al., 2018,; Hoptman 2015; Magid et al., 2007; Roberti, 2004; Zuckerman 29 30 16 1996) (Table 1); 31 32 33 17 (iii) impaired attention, sensorimotor gating, startle habituation, working memory and 34 18 35 cognitive flexibility (Table 1); 36 37 19 (iv) hyper-locomotion and enhanced stereotypies following acute administration of 38 39 20 dopaminergic (DAergic) psychostimulants or morphine (Table 2); 40 41 42 21 (v) increased locomotor and DAergic accumbal sensitization to chronic amphetamine, 43 44 22 cocaine, morphine and ethanol (Table 2); 45 46 23 47 (vi) enhanced operant lever pressing during acquisition, maintenance, extinction and 48 24 reinstatement of cocaine self-administration, as well as enhanced preference for ethanol 49 50 25 and natural rewards (Table 1); 51 52 53 26 (vii) increased functional tone of the mesolimbic DAergic system (Table 3). 54 55 27 As extensively reviewed in Giorgi et al. (2019), schizophrenia and vulnerability to drug 56 57 28 addiction share some core features and/or mechanisms. In particular, for instance, the 58 59 29 enhanced behavioral and neurochemical (e.g. DAergic) effects of acute and chronic 60 61 62 5 63 64 65 1 DAergic psychostimulants, and the increased functional tone of the mesolimbic DAergic 1 2 2 system, are features that are considered to be at the core of both schizophrenia and 3 3 addiction and are present in RHA rats relative to RLAs. 4 5 6 4 7 8 9 5 1.1. Psychopharmacological evidence: propsychotic and antipsychotic drug effects on 10 11 6 locomotor activity, prepulse inhibition and social behavior preference in RHA vs. RLA 12 13 7 rats 14 15 8 In this section we discuss mostly recent findings that have not been reviewed or discussed 16 17 9 in our previous review (Giorgi et al., 2019). 18 19 20 10 The face, predictive and construct validity of RHA vs. RLA rats as a genetic model of 21 22 11 schizophrenia-relevant and addiction-linked features are supported by the enhanced 23 12 sensitivity of RHAs to the locomotor-stimulant and accumbal DA-releasing effects of 24 25 13 26 acute and chronic psychostimulants, which indicate a higher functional tone of the 27 14 mesolimbic/mesostriatal dopaminergic pathways of RHA vs. RLA rats (Table 2). 28 29 30 15 Moreover, in the context of the predictive validity of the RHA model, it is noteworthy 31 32 16 that PPI of the acoustic startle is further impaired by the non selective DA D1/D2 receptor 33 34 17 agonist apomorphine and improved by the DA D2/D3 receptor antagonist haloperidol in 35 18 36 RHA, but not RLA rats (Oliveras et al., 2017). In addition, recent results from our 37 19 laboratory reveal that oxytocin (which has antipsychotic effects in rodents and humans; 38 39 20 Feifel and Reza 1999; Feifel et al., 2010, 2012, 2015; Lee et al., 2005) attenuates the PPI 40 41 21 deficit of RHAs while being devoid of effects on RLA rats (Tapias-Espinosa et al., 2021; 42 43 22 see Table 2). Also, RHA rats show less locomotor-reducing effects of haloperidol and 44 23 45 are more sensitive to apomorphine-induced stereotypies (Gimenez-Llort et al., 2005; 46 24 47 Oliveras et al., 2017) (Table 2). In the context of glutamatergic and serotoninergic 48 25 transmission, which are involved in schizophrenia (e.g. Elert 2014; Elfving et al., 2019; 49 50 26 González-Maeso et al., 2008, and references therein), clozapine (5-HT2A receptor 51 52 27 antagonist) significantly attenuated the dizocilpine (NMDA receptor channel blocker)- 53 28 54 induced PPI deficit only in RLA (but not RHA) rats, and the propsychotic drug 2,5- 55 29 dimethoxy-4-iodoamphetamine (DOI, a HT2A receptor agonist) disrupted PPI in RLA 56 57 30 rats in a dose-dependent manner (0.1, 0.25, 0.5 1.0 mg/kg) while only the 0.5 mg/kg dose 58 59 31 impaired PPI in RHA rats (Oliveras et al., 2017). These attenuated effects of clozapine 60 61 62 6 63 64 65 1 and DOI in RHA rats seem to be consistent with the fact that there is an alteration of the 1 2 2 5HT2A/mGlu2 (metabotropic glutamate-2) receptor complex in these rats (as we will see 3 3 in detail in the following sections; Gonzalez-Maeso et al., 2008; Wood et al., 2017). 4 5 4 Finally, the locomotor-enhancing effects of the propsychotic drug dizocilpine are much 6 7 5 more marked in RHA rats than in their RLA counterparts, and are more effectively 8 9 6 attenuated by the atypical antipsychotics clozapine, ziprasidone and aripiprazole in RHA 10 11 7 vs. RLA rats (Lavín, 2019; Oliveras et al., 2017; Torrecilla 2018; see Table 2). 12 13 14 8 Importantly, the face validity of RHA rats as a model of schizophrenia-related negative 15 9 symptoms was evaluated in a series of social interaction tests. It was predicted that, 16 17 10 compared with their RLA counterparts, RHAs would display less social preference and 18 19 11 more profound social behavior impairments upon the administration of dizocilpine. 20 21 12 Social preference was measured as the relative amount of social or non-social behavior 22 23 13 shown by rats in a rectangular box with one hole in each of its distal sides (Sampedro- 24 25 14 Viana et al., 2021). In this set-up, the rats are physically separated by placing them in two 26 15 27 adjacent rectangular boxes. Each box has a hole at each end, the so called social and non- 28 16 social hole, respectively; the social holes of each box are those facing each other. The rats 29 30 17 are able to poke their noses through the social or non-social holes, thus giving an 31 32 18 indication of respectively social or non-social investigative behavior (Gururajan et al., 33 34 19 2012; Panksepp et al., 1997; Sampedro-Viana et al., 2021). Social behavior preference is 35 20 indicated in this test by the “social preference” index, that is, the percent of interaction 36 37 21 38 time in the social hole relative to the sum of both holes. The predicted results were 39 22 confirmed by the experiments; thus, drug-free RHAs displayed less social behavior 40 41 23 preference than RLAs (Sampedro-Viana et al., 2021) while the social preference of RHA, 42 43 24 but not RLA, rats was dramatically reduced by dizocilpine (to about 40% of vehicle- 44 45 25 treated rats; Torrecilla 2018; Table 2). Remarkably, the impairment of social preference 46 26 47 elicited by dizocilpine is attenuated, or even reversed, by the atypical antipsychotic drugs 48 27 49 clozapine, aripiprazole and ziprasidone in RHA, but not RLA, rats (Lavín 2019; Table 2). 50 51 28 Collectively, the acute and chronic effects of psychostimulant drugs on locomotor 52 53 29 activity and sensitization, the propsychotic effects of apomorphine and dizocilpine, the 54 30 55 antipsychotic-like effects of haloperidol, clozapine, aripiprazole, ziprasidone, and 56 57 31 oxytocin, and their pharmacological effects on PPI and/or social behavior, give 58 32 experimental support to the predictive and face validity of RHA rats as a model of 59 60 33 schizophrenia-relevant features (Table 2). Furthermore, the foregoing results highlight 61 62 7 63 64 65 1 the involvement of glutamatergic, serotoninergic and mesolimbic dopaminergic 1 2 2 mechanisms in the phenotypic traits of RHA rats, which provides support to the construct 3 3 validity of the RHA model. These contentions are further supported by the cognitive and 4 5 4 attentional deficits of RHAs, relative to RLAs and other rat strains/stocks used as external 6 7 5 controls (Table 1). 8 9 10 6 11 12 13 7 1.2. Developmental onset of behavioral phenotypes in the RHA model 14 15 8 Notably, some of the schizophrenia–related behavioral phenotypes of the RHA model 16 17 9 follow a developmental pattern. Thus, compared with RLAs (and with outbred rats, in 18 19 10 some cases), male RHA rats display slight PPI deficits at puberty (postnatal days –PND- 20 21 11 50-56), and such an impairment is much more marked in adulthood (>PND100), but is 22 23 12 not present at prepuberty (PND30) (del Río et al., 2014; Oliveras et al., 2015; Soria-Ruiz 24 13 25 2021). On the other hand, the PPI impairment in female RHA rats clearly emerges at 26 14 27 puberty (PND50-56) and continues during adulthood (> PND100), but is not observed at 28 15 pre-pubertal age (Río-Álamos et al., 2019; Soria-Ruiz 2021). Likewise, our ongoing 29 30 16 studies show that the deficit of habituation of the acoustic startle response in RHA rats 31 32 17 emerges in adulthood. 33 34 18 A very consistent finding is the marked hyperactivity that RHA rats of both sexes exhibit 35 36 19 37 in open field-like tests and in tunnel labyrinths (involving no explicit reward), which is 38 20 already present at early pubertal ages (around PND30-35; e.g. Escorihuela et al., 1997; 39 40 21 Fernández-Teruel et al., 1991a, 1992b, 2002c) and persists through adolescence and 41 42 22 adulthood (e.g. Castanon and Mormède 1994; Escorihuela et al., 1999; Estanislau et al., 43 44 23 2013; Lopez-Aumatell et al., 2009b; Steimer and Driscoll 2003). Conversely, when 45 24 46 exposed to test situations involving more explicit and hippocampus-dependent approach- 47 25 48 avoidance conflict, such as the elevated plus-maze or the dark/light (two-compartment) 49 26 50 box tests, which involve clear “safe” vs. threatening spaces (Bannerman et al., 2004, 51 27 52 2014; Gray and McNaughton 2000), the hyperactivity of RHA rats (i.e. increase of 53 28 horizontal activity or crossings between the “safe” and threatening spaces) is not observed 54 29 55 at prepubertal or pubertal ages (PND28-35 or PND56, respectively), and only appears 56 consistently at young adulthood (Escorihuela et al., 1999; Fernández-Teruel et al., 2002c; 30 57 58 31 Steimer and Driscoll 2003). 59 60 61 62 8 63 64 65 1 Some of the stress-related behavioral/endocrine phenotypes of RHA rats also follow a 1 2 2 developmental onset, i.e. they emerge in young adulthood, after PND 90-100, as in the 3 3 case of the stress-induced ACTH response (Castanon and Mormède 1994; Castanon et 4 5 4 al., 1994). Also in this context, relative to RLA and genetically heterogeneous rats (i.e. 6 7 5 the “National Institutes of Health heterogeneous stock rat”, or, HS rats), RHA rats show 8 9 6 a marked deficit in novelty/stress-induced grooming behavior at pubertal age and young 10 11 7 adulthood (PND 56-70) that is not present at prebubertal ages (PND 28-35; Estanislau 12 13 8 et al., 2013; Steimer and Driscoll 2003). It seems relevant here to underscore the similarity 14 9 15 between the decreased grooming behavior and, to a certain extent, hyperactivity, of RHA 16 10 17 rats and that observed in the neonatal ventral hippocampus lesion (NVHL) rat model of 18 11 schizophrenia. The NVHL model is probably the most used neurodevelopmental model 19 20 12 of schizophrenia, and is considered to have good face, construct and predictive validity 21 22 13 for the different symptoms of the disorder as well as regarding the associated 23 24 14 neurobiological mechanisms or processes (e.g. Tseng et al., 2009). Interestingly, much 25 15 like RHA rats, NVHL rats also show a deficit in grooming behavior at young adulthood, 26 27 16 28 but not at prepubertal age, that depends on the integrity of the PFC (Estanislau et al., 29 17 2013; Flores et al., 2005; Tseng et al., 2009). 30 31 32 18 Regarding the negative symptom spectrum of schizophrenia, we have recently found that 33 34 19 the deficit of social interaction preference that characterizes adult male and female RHA 35 20 rats (vs. RLA and outbred HS rats) is not present in adolescent animals at PND50 36 37 21 38 (Sampedro-Viana et al., 2021; Soria-Ruiz 2021; Table 1). Thus, adolescent male RHA 39 22 rats exhibit a social interaction preference of 71%, which is not different from a 77% 40 41 23 42 social preference of adolescent RLA rats (Soria-Ruiz 2021). Interestingly, during 43 24 adulthood these percentages evolve up to approximately 50% in RHA (i.e. they do not 44 25 45 show preference for the “social” hole of the testing cage) and 60-70% in RLA rats, 46 26 47 showing significant differences between both strains (Sampedro-Viana et al., 2021). Of 48 27 49 note, no differences in social preference between female RHA and RLA rats of either age 50 28 51 have been found (Soria-Ruiz 2021). Thus, there is an age- and sex-linked pattern of 52 29 53 appearance of the social interaction deficit in RHA rats, which opens a new research path 54 30 55 on the developmental onset and gender-dependent neurobiological processes related to 56 31 some schizophrenia-linked symptoms in this rat strain. 57 58 32 It is also noteworthy that environmental conditions during postnatal development may 59 60 33 enduringly influence some of these genetically-based phenotypic profiles. Thus, neonatal 61 62 9 63 64 65 1 handling (NH)-stimulation (administered from PND1 to PND21) produces very long- 1 2 2 lasting improvements of PPI and cognitive performance in RHA rats, along with strain- 3 3 dependent volume alterations of HC and AMY (Rio-Álamos et al., 2017b, 2019), and it 4 5 4 also increases social interaction preference more markedly in RHAs than in RLA rats 6 7 5 (Sampedro-Viana et al., 2021). On the other hand, social isolation rearing (SIR) in rats is 8 9 6 considered a model of early adversity-induced schizophrenia-like symptoms/features 10 11 7 with face and predictive validity (see reviews by Jones et al., 2011; Fone and Porkess 12 13 8 2008). SIR produces profound deleterious and enduring effects in RHA rats (but not in 14 9 15 RLA rats), as shown by marked increases in anxiety, enhanced hyperactivity, and 16 10 17 impairments of PPI and spatial cognition (Oliveras et al., 2016; Sánchez-Gonzalez et al., 18 11 2019). These findings demonstrate that environmental influences on neurodevelopmental 19 20 12 processes may affect the development of several of the above-mentioned genetically- 21 22 13 based schizophrenia-relevant phenotypes, while also showing an increased sensitivity of 23 24 14 RHA (vs. RLA) rats to the effects of particular developmental interventions on those 25 15 phenotypes. 26 27 28 16 Although further developmentally-oriented studies are warranted, the above reviewed 29 30 17 findings suggest an altered neurobehavioral development in RHA rats which may be 31 32 18 consistent with their schizophrenia-related phenotypic profiles. This will be reviewed and 33 34 19 discussed more in depth in the following sections. 35 36 20 37 38 39 21 2. Brain features of RHA vs RLA rats: a neurodevelopmental perspective 40 41 42 22 3.1 The mesocorticolimbic DA system: Recent developments related to the 43 44 23 schizophrenia- and drug addiction-relevant profile of the RHA model 45 46 24 47 In this and the following sections we present and discuss mostly recent findings with the 48 25 RHA model (vs RLA rats and other strains or models) that have neurodevelopmental 49 50 26 implications for the model and have not been included or discussed in our previous 51 52 27 reviews (Giorgi et al., 2019; Driscoll et al., 2009). 53 54 28 55 A recent report has shown that, besides exhibiting increased cocaine self-administration 56 29 and resistance to extinction (as previously shown by Fattore et al., 2009), compared with 57 58 30 RLA rats RHAs display higher propensity to cocaine-induced relapse, a trait that may be 59 60 31 due to the larger DA release in the NAcc of RHA rats in response to cocaine rather than 61 62 10 63 64 65 1 to postsynaptic DA receptors-mediated mechanisms (Dimiziani et al., 2019). That study 1 2 2 also demonstrated that when cocaine-induced relapse occurs, it is mainly mediated by 3 3 postsynaptic D2 rather than D3 receptors. Accordingly, cocaine-induced relapse is 4 5 4 inhibited in both Roman rat lines by pretreatment with the D2 receptor antagonist, 6 7 5 L741,626, but not with the D3 receptor antagonist, SB-277,011A (Dimiziani et al., 2019). 8 9 6 However, there is consistent evidence that pretreatment with D3 receptor antagonists 10 11 7 reduces reinstatement of cocaine-seeking behavior in other rat strains (Vorel et al., 2002) 12 13 8 and in squirrel monkeys (Achat-Mendes et al., 2010), which, therefore, highlights the 14 9 15 importance of the differences between strains and species. Another recent and potentially 16 10 17 important finding from the same group was that, compared with RLA rats, RHAs exhibit 18 11 lower striatal D2/D3 receptor adaptations (i.e. lesser functional supersensitivity) 19 20 12 following chronic D9-tetrahydrocannabinol (THC) administration (Tournier et al., 2018). 21 22 13 Together with the increased striatal mRNA expression of CB1 (cannabiboid type 1) 23 24 14 receptor in RHA rats, these findings may suggest that differences between both rat lines 25 15 in the balance of CB1-D2/D3 transmission could be related to the divergent responses to 26 27 16 28 abused drugs of RHA and RLA rats (Tournier et al., 2018). Of note, the endocannabinoid 29 17 systems, acting through several signaling pathways, seem to be involved in the regulation 30 31 18 of neural cell survival, neurogenesis and neuronal maturation across development (e.g. 32 33 19 Paraíso-Luna et al., 2020; Sagredo et al., 2018). Hence, these divergent THC effects and 34 35 20 CB1 expression in RHA vs. RLA rats may suggest that differences in the 36 21 37 endocannabinoid systems might have a role on the particular neurobehavioral 38 22 39 developmental profiles of the former strain. This possibility deserves further research. 40 41 23 On the other hand, in a replication and extension of Tournier et al. (2013) study, Bellés 42 43 24 et al. (2021) have reported that impulsivity and novelty seeking (novelty preference) traits 44 45 25 are positively related in the Roman rats (Bellés et al., 2021). Both phenotypes are 46 26 47 negatively related with D2/3 autoreceptor availability in ventral striatum and dorsal 48 27 49 striatum, which is decreased in in the high-impulsive/ novelty-preferring RHA animals 50 28 51 (Bellés et al., 2021). A novel finding of this study is, however, the existence of some 52 29 53 differences between RHA and RLA rats regarding amphetamine (AMPH)-induced DA 54 30 release in relation to their novelty preference and impulsivity profiles. This suggests that 55 31 56 “…Impulsivity and novelty preference are related but mediated by overlapping, yet 57 dissociable, DA-dependent mechanisms in striatum that may interact to promote the 32 58 59 33 emergence of an addiction-prone phenotype” (Bellés et al., 2021). As mentioned earlier, 60 61 62 11 63 64 65 1 locomotor and DAergic sensitization are considered to play a key role in several aspects 1 2 2 of addiction. In particular, resistance to extinction of cocaine-seeking behavior, as shown 3 3 by RHA rats, is thought to reflect an altered glutamatergic and/or dopaminergic activity 4 5 4 in the prefrontal cortex (Millan et al., 2011; Marchant et al, 2012; Peters et al, 2008) and 6 7 5 mesolimbic (Self et al., 2004) pathways, which in turn are linked to an inability to inhibit 8 9 6 inappropriate (impulsive) responding to drug-associated stimuli (Jentsch and Taylor, 10 11 7 1999; Kalivas et al., 2005). Of note in this context, prefrontal cortex dysfunctions are 12 13 8 associated with impulsivity (Crews and Boettiger, 2009; Dalley et al., 2002), thus 14 9 15 suggesting a common mechanism that could affect impulsive behavior and persistence of 16 10 17 cocaine-seeking behavior in RHA rats. Accordingly, cocaine-sensitized RHA rats (but 18 11 not RLA rats) show a marked reduction of DAergic transmission in the mPFC (Giorgi et 19 20 12 al., in preparation). 21 22 23 13 The functional tone of central DAergic systems is though to be related to the intensity of 24 25 14 locomotor behavior (e.g. Flores et al., 2005; Giménez-Llort et al., 2005, and references 26 15 27 therein). Accordingly, from a developmental perspective, the marked and consistent 28 16 behavioural disinhibition and hyperactivity observed across different novelty conditions 29 30 17 in prepubertal and pubertal RHA rats (as mentioned in section 2.2), suggest that central 31 32 18 DA systems may be altered during early development in these animals. Although this 33 34 19 hypothesis has yet to be examined, it is indirectly supported by the altered expression of 35 20 36 neurodevelopment-related pre- and post-synaptic markers found in the PFC of RHA rats 37 21 38 (as we will discuss in the following sections; Elfving et al., 2019). Since DA systems 39 22 interact with GABA and glutamate systems in the PFC, it seems conceivable that 40 41 23 developmental abnormalities of mesocorticolimbic DA function may be associated to 42 43 24 altered interactions with, and maturation of prefrontal (and probably other) GABA and 44 25 45 glutamate systems, which are considered of crucial importance for the function of the 46 26 47 PFC and for the balance between excitation and inhibition (e.g. Tseng et al., 2009). This 48 27 49 would also be consistent with the reduced activity and volume of the mPFC found in adult 50 28 51 RHA rats (Meyza et al., 2009; Rio-Álamos et al., 2019; Tapias-Espinosa et al., 2019; 52 29 53 Table 3), as well as with both their enhanced behavioral and neurochemical sensitivity to 54 30 the effects of acute and chronic DAergic psychostimulants and their vulnerability to 55 31 56 addiction (reviewed by Giorgi et al., 2019), 57 58 32 59 60 61 62 12 63 64 65 1 3.2 Glutamate-serotonin interactions in the PFC 1 2 3 2 Considerable experimental evidence supports the view that serotonin transmission is 4 3 crucially involved in impulsivity. The general consensus is that an increase in central 5 6 4 serotonergic function is associated with a decrease in impulsivity and impulsive sensation 7 8 5 seeking (Dalley and Robbins, 2017; Soubrié, 1986; Zuckerman, 1996). In this sense, 9 10 6 activation of 5-HT2A receptors seems to facilitate some forms of impulsive behavior, 11 12 7 whereas antagonism of these receptors produces reductions of several types of impulsive 13 14 8 responses in rodents and humans (reviewed by Dalley and Robbins, 2017, and Klein et 15 9 al., 2014). Accordingly, the density of 5-HT2A receptors (a site of action of atypical 16 17 10 antipsychotic drugs) is higher in the PFC of RHA than RLA rats, and there is a positive 18 19 11 correlation between 5-HT2A receptor density and premature/impulsive responses in the 5- 20 21 12 CSRT task in the RHA strain (Klein et al., 2014). 22 23 24 13 The differences in 5-HT2A receptor density between RHA and RLA rats appear to be 25 14 26 linked to functional differences in glutamate transmission. Thus, it has recently been 27 15 shown that, due to a stop codon mutation at cysteine 407 in Grm2 (cys407* mutation), 28 29 16 the gene encoding the metabotropic glutamate-2 receptor (mGlu2) (Wood et al., 2017; 30 31 17 see also Fomsgaard et al., 2018), RHA, but not RLA, rats display a severe disruption of 32 33 18 the heteromeric 5-HT2A/mGlu2 receptor complex (Fomsgaard et al., 2018; Klein et al. 34 35 19 2014; see González-Maeso et al., 2008) (Table 3). Hence, there is a dramatic reduction in 36 20 37 the density of mGlu2 receptors in the cerebral cortex, hippocampus (HC) and striatum 38 21 (STR), associated with an increase of 5-HT2A receptor density in the frontal cortex of 39 40 22 RHA rats (Elfving et al., 2019; Fomsgaard et al., 2018; Klein et al. 2014). Of note in this 41 42 23 context, chromatin immunoprecipitation assays have revealed an increased trimethylation 43 44 24 of histone 3 (H3) at lysine 27 (H3K27me3) at the promoter region of the gene encoding 45 25 the 5-HT2A receptor in the STR of RHA rats (Fomsgaard et al., 2018). Such an increment 46 47 26 48 in H3 trimethylation may be the cause of the above-mentioned increase of 5-HT2A 49 27 receptor density (see Fomsgaard et al., 2018). Interestingly, this molecular profile is 50 51 28 reminiscent of the alterations found in the cortex of drug-free schizophrenic patients and, 52 53 29 accordingly, it has been shown that the heteromeric 5-HT2A/mGlu2 receptor complex is 54 30 critically involved in the pharmacologic effects of atypical antipsychotics (Fribourg et al., 55 56 57 31 2011; Gonzalez-Maeso et al. 2008; Moreno et al., 2012, 2016; Muguruza et al., 2013). 58 32 Also consistent with the above findings, the expression of the gene encoding the mGlu2 59 60 33 receptor is significantly decreased in both PFC and STR of RHA rats (Fomsgaard et al., 61 62 13 63 64 65 1 2018). As regards the Akt/GSK3 signaling pathway, which is a downstream point of 1 2 2 convergence of the serotonin and glutamate transmission, it has been found that the 3 3 phosphorylation levels of GSK3β at tyrosine 216 and β-catenin levels are higher in the 4 5 4 PFC of RHA than RLA rats (Fomsgaard et al., 2018). These results point to a region- 6 7 5 specific regulation of the 5-HT2A receptor in RHA rats that is probably due to the absence 8 9 6 of mGlu2 receptors (Wood et al., 2017), and that may result in a strain-dependent 10 11 7 differential regulation of downstream signaling pathways (Fomsgaard et al., 2018). It is 12 13 8 also remarkable that the levels of the NMDA2B subunit of the NMDA receptor, as well 14 9 15 as the expression of Grin2b mRNA (NMDA2B), are higher in the HC and PFC of RHA 16 10 17 vs. RLA rats (Elfving et al., 2019; Table 3), since both strain-dependent differences may 18 11 determine distinct downstream regulation patterns of neural activity. Therefore, the 19 20 12 alterations observed in the 5-HT2A/mGlu2 complex and NMDA receptors in RHA rats 21 22 13 may at least partly account for some of the schizophrenia-related traits observed in this 23 24 14 strain, such as the enhanced responsivity to the locomotor-stimulating effects of 25 15 dizocilpine, the dizocilpine-induced impairment of social behavior, and the differential 26 27 16 28 effect of clozapine on both dizocilpine-impaired PPI performance and dizocilpine- 29 17 stimulated locomotor activity in RHA vs. RLA rats (Lavín 2019; Oliveras et al., 2017; 30 31 18 Table 2). 32 33 34 19 Mounting evidence suggests that glutamate-mediated synaptic plasticity, in particular 35 20 36 long-term depression (LTD), plays an important role in synaptic pruning in the PFC 37 21 38 during adolescence. Because the disruption of synaptic plasticity may derail the normal 39 22 maturation of executive function (Selemon, 2013), it is likely that the absence of the 40 41 23 mGlu2 receptor in the RHA strain may cause synaptic alterations, thereby hindering the 42 43 24 development and maturation of the brain (Elfving et al., 2019). Although the mechanisms 44 45 25 underlying these alterations remain largely unknown, recent studies have revealed a 46 26 47 functional interaction between the mGlu2 receptor and BDNF in vitro in which the 48 27 49 activation of the mGlu2 receptor by a selective agonist enhances BDNF-induced BDNF 50 28 51 gene expression, whereas BDNF down-regulates the expression of the mGluR II gene 52 29 53 (Suzuki et al., 2017). 54 55 30 56 57 31 58 59 60 32 61 62 14 63 64 65 1 3.3. Synaptic alterations and neurotrophic factors in the PFC 1 2 3 2 Dysregulation of neurotrophic factors like BDNF has long been associated with the 4 3 cellular, cytoarchitectural and volumetric alterations seen in schizophrenia (Angelucci et 5 6 4 al., 2005). Post-mortem studies in the brain of schizophrenia patients have shown 7 8 5 significant alterations in BDNF mRNA and protein levels in the cerebral cortex and HC 9 10 6 (Durany et al., 2001; Reinhart et al., 2015; Takahashi et al., 2000). In humans, the 11 12 7 Val(66)Met single-nucleotide polymorphism in the BDNF gene is associated with 13 14 8 increased schizophrenia risk (Lencz et al., 2009; Ursini et al., 2016). Furthermore, when 15 9 this mutated human gene is introduced in an animal model, the resulting genotype is 16 17 10 associated with deficits in sensorimotor gating processes (Notaras et al., 2017). 18 19 11 Accordingly, compared to RLA rats, the protein levels of BDNF are lower in the PFC 20 21 12 and higher in the HC of RHA rats (Elfving et al., 2019; Serra et al., 2018), and the levels 22 23 13 of the Polysialilated-Neural Cell Adhesion Molecule (PSA-NCAM), which interacts with 24 25 14 BDNF and its receptor facilitating BDNF signaling (Serra et al., 2018; Bonfanti, 2006), 26 15 27 are generally higher in the dorsal HC of RHAs relative to RLAs (Serra et al., 2018). 28 16 These changes in neurotrophic factors seem to be compatible with the aforementioned 29 30 17 alterations in activity and volume of the PFC and HC, and the enlargement of lateral 31 32 18 ventricles, in RHA rats (Meyza et al., 2009; Rio-Alamos et al., 2017b, 2019; Tapias- 33 34 19 Espinosa et al., 2019; Table 3). 35 36 20 37 BDNF plays a key role in synaptic plasticity and communication during 38 21 neurodevelopment (Favalli et al., 2012; Kowianski et al., 2018; Nieto et al., 2013) and 39 40 22 synaptic alterations have been reported in the brain of schizophrenia patients (Focking et 41 42 23 al., 2015). Accordingly, RHA rats also show altered levels of synaptic components, 43 44 24 including the postsynaptic density (PSD) proteins Homer1 in PFC (Elfving et al., 2019; 45 25 Table 3) and Homer3 in whole brain (Sabariego et al., 2011). Abnormalities in the PSD 46 47 26 48 are linked to neurodevelopmental diseases such as autism spectrum disorder and 49 27 schizophrenia (Kaizuka and Takumi, 2018). The PSD protein Homer1 mediates the 50 51 28 glutamatergic, serotonergic and dopaminergic receptor signaling at the postsynaptic site 52 53 29 (de Bartolomeis et al., 2013a,b; Iasevoli et al., 2011), and Homer1 polymorphisms are 54 55 30 associated with differential responses to treatment in schizophrenia (Spellmann et al., 56 31 57 2011). In line with the increased expression of Homer1 in RHA rats, differential effects 58 32 of antipsychotic and propsychotic drugs targeting dopamine, glutamate and serotonin 59 60 61 62 15 63 64 65 1 receptors have been found in RHA vs. RLA rats (Oliveras et al., 2017; Lavín 2019; 1 2 2 Torrecilla 2018; see Table 2). 3 4 3 RHA rats also display increased expression and protein levels of Nrg1 (neuregulin-1) in 5 6 4 the PFC (Elfving et al., 2019; Table 3). Nrg1 has a role in regulating the 7 8 5 excitatory/inhibitory neurotransmission at the PSD and is linked to schizophrenia risk 9 10 6 (Mostaid et al., 2016). In fact, Nrg1 modulates sensorimotor gating, and disruption of 11 12 7 Nrg1 signaling impairs hippocampal-prefrontal synchrony and topdown attention, as seen 13 14 8 in animal (Rhein et al., 2013; Karl et al., 2011; Tan et al., 2018) and human studies 15 9 (Roussos et al., 2011; Hong et al., 2008); thus, an increased NRG1 expression is positively 16 17 10 associated with schizophrenia-like pathology and PPI impairment (Deakin et al., 2009; 18 19 11 Karl et al., 2011; Rhein et al., 2013; Swerdlow et al., 2012). 20 21 22 12 Moreover, upregulation in presynaptic SNARE components is observed in the brain of 23 24 13 schizophrenia patients (Ramos-Miguel et al., 2015): the levels of two of the core proteins 25 14 26 in the SNARE complex, SNAP25 and VAMP (Cupertino et al., 2016), are altered in the 27 15 PFC and HC of RHA rats (Table 3). Thus, SNAP 25 expression is upregulated in the PFC 28 29 16 of the RHA strain (Elfving et al., 2019). SNAP25 controls exo/endocytic processes at the 30 31 17 presynaptic terminal and plays an important role in regulating postsynaptic receptor 32 33 18 trafficking and synaptic plasticity (Antonucci et al., 2016). Overexpression of SNAP 25 34 35 19 leads to memory deficits (McKee et al., 2010), as also shown for the RHA strain (Oliveras 36 20 37 et al., 2015; Rio-Álamos et al., 2019). In the HC, VAMP1 and SNAPIN gene expression 38 21 and protein levels are decreased in RHA rats (Elfving et al., 2019). VAMP proteins are 39 40 22 essential for the fast synaptic-vesicle exocytosis and recycling and for the insertion of 41 42 23 glutamate receptors into the postsynaptic plasma membrane (Deak et al., 2004; Hussain 43 44 24 and Davanger, 2015; Gu and Huganir, 2016), whereas SNAPIN seems to be an important 45 25 component of the SNARE-mediated neurotransmitter release (Ilardi et al., 1999). The 46 47 26 48 alterations in NMDA receptor subunits observed in RHA rats could be linked to the 49 27 observed variations in the SNARE complex, as this complex regulates NMDA receptor 50 51 28 trafficking (Gu and Huganir, 2016) and mediates the insertion NMDA2B subunits at 52 53 29 postsynaptic sites (Hussain et al., 2016). Thus, it is conceivable that the increased 54 55 30 sensitivity to dizocilpine-induced hyperactivity and dizocilpine-impairment of social 56 31 57 behavior in RHA rats are related to alterations in the SNARE complex (Lavín 2019; 58 32 Oliveras et al., 2017; Torrecilla 2018; see Table 2). 59 60 61 62 16 63 64 65 1 1 2 3 2 3.4 Pyramidal dendritic spines in the PFC 4 5 3 Abnormal neurodevelopment and an immature state of the PFC have been described in 6 7 4 the brains of schizophrenia patients (Hagihara et al., 2014). There is consensus that 8 9 5 impaired PFC function and connectivity is one of the main features of schizophrenia and 10 11 6 is associated with the cognitive deficits that characterize this disorder (Chari et al., 2019; 12 13 7 Ferrarelli et al., 2015; Pu et al., 2019). 14 15 8 Many genes examined in the RHA and RLA strains by Elfving et al. (2019) are 16 17 9 dynamically expressed in the PFC during lifetime, as evidenced from the human Brain 18 19 10 Cloud dataset (Colantuoni et al., 2011; Elfving et al., 2019). These genes are up- or 20 21 11 downregulated during the time windows of neurodevelopment in which executive 22 23 12 function is established (Elfving et al., 2019; Silbereis et al., 2016; Taylor et al., 2015) and, 24 13 25 consequently, they may have an important role in the establishment of some of the 26 14 27 cognitive processes that are disrupted in the RHA strain. Although the animals used in 28 15 the study by Elfving et al. were adult RHA (and RLA) rats, the synaptic markers Homer1, 29 30 16 Nrg1, Syp, BDNF, Grin2B and Drd1 were upregulated in the PFC with a pattern that 31 32 17 resembled that observed in human children or adolescents (Elfving et al., 2019). Further 33 34 18 studies aimed at assessing the expression of these synaptic markers throughout the 35 19 36 lifespan are warranted to confirm that the upregulation pattern of those genes in the PFC 37 20 of RHA rats is indeed the expression of an “immature” phenotype. 38 39 40 21 There is strong evidence that GSK3β and β-catenin are involved in spine stability and 41 42 22 synaptic plasticity both during development and in adulthood (Maguschak and Ressler 43 44 23 2012; Mills et al., 2014; Ochs et al., 2015). Thus, the increased phosphorylation levels of 45 24 46 GSK3β at tyrosine 216 and increased β-catenin levels in the PFC of RHA rats (Fomsgaard 47 25 48 et al., 2018) could be of great importance for understanding the neurobiological substrates 49 26 of the schizophrenia-like neurobehavioral phenotype of the RHA model. This possibility 50 51 27 prompted the study of differences in spine density of pyramidal neurons in the PFC of the 52 53 28 RHA vs RLA rats. It was found that, compared with their RLA counterparts, RHA rats 54 55 29 exhibit a higher number of dendritic spines, due to an increased density of “thin” spines, 56 30 57 but, on the other hand, they show a lower percentage of large and “mature” (i.e., 58 31 mushroom and stubby) spines relative to the “total” number of spines of any type 59 60 32 (Sánchez-González, 2018; Sánchez-González et al., 2021; Table 3). Of note, two 61 62 17 63 64 65 1 important regulators of dendritic spine morphogenesis are the scaffolding protein Homer 1 2 2 1 (Sala et al., 2001) and the neurotrophin BDNF (Tyler and Pozzo-Miller 2003), which 3 3 are upregulated in the PFC of RHA rats (Elfving et al., 2019). 4 5 6 4 Animal studies show that the density of spines is significantly higher during early 7 8 5 adulthood and then progressively declines via pruning during adulthood (Arnsten 2011; 9 10 6 Holtmaat et al., 2005; Silva-Gomez et al., 2003; Tjia et al., 2017). Also, thin spines 11 12 7 predominate in the human adolescent brain (Holtmaat et al., 2005). Dendritic spines are 13 14 8 dynamic structures (Kasai et al., 2010), and their morphology changes during 15 9 development, with thin spines transitioning to mushroom spines, which are more stable 16 17 10 in shape and density (Bourne and Harris 2007; Glausier and Lewis 2013). Therefore, 18 19 11 spine density and morphology can reflect neuronal development, plasticity and 20 21 12 connectivity (Glausier and Lewis 2013; Kasai et al., 2003; Silva-Gomez et al., 2003). An 22 23 13 over-representation of small, more unstable spines and/or a decreased proportion of large, 24 25 14 more stable spines in the PFC is likely causing the impaired cognitive functions seen 26 15 (Kasai et al., 2003, 2010). Dendritic spine alterations in cortical pyramidal neurons have 27 28 16 consistently been reported in postmortem studies of humans with schizophrenia and 29 30 17 appear to be related to the cognitive symptoms of the disorder (Black et al., 2004; Glantz 31 32 18 and Lewis 2000; Hill et al., 2006; Moyer et al., 2015). Altogether, these observations 33 34 19 support the notion of an immature developmental state of the PFC in RHA rats that could 35 20 contribute to a PFC dysfunction and may be involved in the schizophrenia-like behavioral 36 37 21 38 alterations characterizing this strain. 39 40 22 Small thin spines are described as “learning” spines, since they are transient and are 41 42 23 involved in rapid plasticity, and they seem to correspond to “silent synapses”, expressing 43 44 24 NMDA but not AMPA receptors (Glausier and Lewis 2013; Kasai et al., 2003, 2010). In 45 25 contrast, large spines, represented by the stubby and mushroom types, are considered 46 47 26 48 “memory” spines, which are more stable than the small ones and are involved in long- 49 27 term synaptic plasticity, associated with AMPA receptors (Glausier and Lewis 2013; 50 51 28 Kasai et al., 2003). This is very consistent with the findings of increased expression levels 52 53 29 of the NMDA receptor subunit GluN2B in the PFC of the RHA rats, while there is no 54 55 30 difference in AMPA receptor subunits (Elfving et al., 2019). The NMDA receptor with 56 31 57 GluN2B subunits is associated with spine density regulation (Liu et al., 2017) and with 58 32 “silent synapses” (Han and Heinemann 2013; Polli and Kohlmeier 2019). Moreover, 59 60 61 62 18 63 64 65 1 there is a genetic association between this receptor subunit and schizophrenia (Martucci 1 2 2 et al., 2006). 3 4 3 In addition, glial cells play an essential role in synaptic regulation (Bernstein et al., 2009). 5 6 4 The major type of glia cells, astrocytes, are main components of the “tripartite synapse” 7 8 5 (Papouin et al., 2017; Santello et al., 2019), and as such are involved in synaptic function, 9 10 6 plasticity and maturation. Changes in astrocyte number in the PFC have been linked to 11 12 7 several mental disorders, including schizophrenia (Lima et al., 2014; Schnieder and 13 14 8 Dwork 2011). Microglia are also involved in synaptic maturation (Mallya et al., 2019). 15 9 No difference in microglia numbers in the PFC of RHA and RLA rats has been found, 16 17 10 whereas a marked difference in astrocytes (RHA > RLA) has been observed (Sánchez- 18 19 11 González, 2018; Sánchez-González et al., 2021; Table 3). Microglia’s role during 20 21 12 adolescence is related to synaptic pruning and synaptic elimination (Mallya et al., 2019) 22 23 13 and, since RHA rats show a higher rather than reduced number of dendritic spines, one 24 25 14 would not expect an increased number of microglia. Conversely, it seems very likely that, 26 15 given the important role of astrocytes in the development of cortical neural circuits 27 28 16 (Macht 2016) and in the stabilization (Bernardinelli et al., 2014) and maturation of 29 30 17 excitatory synapses (Reemst et al., 2016), the increased number of astrocytes observed in 31 32 18 the PFC of the RHA rats is associated with the dendritic spine alterations in this strain. 33 34 19 Thus, the increase in astrocytes may be a compensatory mechanism to help stabilize a 35 20 larger number of thin spines in the PFC of the RHA strain. Astroglia release D-serine, a 36 37 21 38 co-agonist of the NMDA receptor (Meunier et al., 2017), which could lead to 39 22 overstimulation of NMDA receptors containing the GluN2B subunit. On the other hand, 40 41 23 glutamate regulation is essential for the maturation of synaptic dendrites (Mattison et al., 42 43 24 2014) and astrocytes regulate glutamate release through activation of their mGlu2/3 44 45 25 receptors (Tang and Kalivas 2003). The stop codon in the DNA of RHA rats that results 46 26 47 in the absence of mGlu2 receptors (Fomsgaard et al., 2018; Wood et al., 2017) may lead 48 27 49 to malfunction of astroglia in this strain, which may sustain their immature synaptic 50 28 phenotype. Indeed, dysfunction of astroglia during brain development can contribute to 51 52 29 neurodevelopmental disorders (Reemst et al., 2016). The fact that astroglia (but not 53 54 30 microglia) is altered in RHA rats supports this idea (Sanchez-Gonzalez, 2018; Sanchez- 55 56 31 Gonzalez et al., 2021). 57 58 32 59 60 61 62 19 63 64 65 1 3.5 Excitatory/inhibitory balance in the PFC 1 2 3 2 Excitatory pyramidal cells receive inhibitory input from PV interneurons, a subtype of 4 3 GABAergic interneurons (Gonzalez-Burgos et al., 2015), and interneuron dysfunction is 5 6 4 believed to be one of the causes behind the neurocircuitry disruption linked to 7 8 5 schizophrenia (Marin 2012). No differences between RHA and RLA rats were observed 9 10 6 in numbers of PV-containing GABAergic interneurons in the mPFC (Sanchez-Gonzalez 11 12 7 et al., 2021). This is in accordance with lower PV mRNA expression and density of PV- 13 14 8 immunoreactive puncta rather than a reduced number of PV interneurons, as found in the 15 9 brain of schizophrenia patients (Beasley et al., 2002; Chung et al., 2016; Enwright et al., 16 17 10 2016; Glausier et al., 2014; Lewis et al., 2012). About half of the genes representing the 18 19 11 transcriptomic immaturity of the PFC of schizophrenia patients are related to the 20 21 12 development of PV-interneurons and astroglia (Hagihara et al., 2014). One of these 22 23 13 GABAergic interneuron-specific genes expressed by PV interneurons is ErbB4 -the 24 25 14 receptor for the trophic factor neuregulin 1, Nrg1-, which is important for spine formation 26 15 27 in cortical pyramidal neurons (Agarwal et al., 2014; Yin et al., 2013). Nrg1 increases 28 16 spine density but it is through ErbB4 that it regulates spine growth (Cahill et al., 2013), 29 30 17 and impaired Nrg1/ErbB4 signaling leads to dendritic spine destabilization and 31 32 18 glutamatergic hypofunction (Li et al., 2007a). Interestingly, the RHA rats present 33 34 19 increased expression levels of Nrg1 in the PFC (Elfving et al., 2019), which could explain 35 20 36 the increased spine density observed in this strain. ErbB4 signaling is required for 37 21 38 attention (Tan et al., 2018 ) and, since attentional deficits (linked to impulsivity) are one 39 22 of the main behavioral features of RHA rats (e.g. Esnal et al., 2016; Klein et al., 2014; 40 41 23 Oliveras et al., 2015; Río-Álamos et al., 2019; Tapias-Espinosa et al., 2019), it may be 42 43 24 hypothesized that Nrg1/ErbB4 signaling is impaired in this strain. It is therefore 44 45 25 warranted to assess whether RHA rats show PV neuron specific ErbB4 dysfunction across 46 26 47 development. 48 49 27 GABAergic interneurons in the PFC are innervated by dopaminergic fibers originating in 50 51 28 the ventral tegmental area (VTA) and express D1 and D2 receptors, which facilitate local 52 53 29 GABAergic function in the PFC. Of note, D1 receptors are involved in NMDA receptor 54 30 55 trafficking to postsynaptic membranes (see Tseng et al., 2009, and references therein). In 56 57 31 the PFC, RHA rats show an increased density of D1 and NMDA2B receptors (Elfving et 58 32 al., 2019) but, as previously mentioned, they do not differ from RLA rats regarding the 59 60 33 number of PV-containing GABA interneurons. However, we have recently found that 61 62 20 63 64 65 1 PV+ labeling is decreased by about 60 % in RHA rats in PFC neurons activated (as 1 2 2 measured by c-fos expression) following a PPI session (Table 3). This finding suggests 3 3 that, when activated by an attention-related task (i.e. PPI), the PFC of RHA rats exhibits 4 5 4 a relatively low or disrupted inhibitory activity due to a decreased activation of PV 6 7 5 GABAergic neurons (Tapias-Espinosa 2020; Table 3). 8 9 10 6 In view of the above mentioned findings, together with the altered densities of D1, 5- 11 12 7 HT2A, NMDA and mGlu2 receptors and the upregulation of the synaptic markers 13 14 8 Homer1, BDNF, SNAP25 and Nrg1, it is conceivable that the PFC of RHA rats shows a 15 9 developmental dysregulation of excitation/inhibition balance. This would cohere with the 16 17 10 aforementioned volumetric and functional (c-fos) frontocortical and HC differences 18 19 11 observed between RHA and RLA rats (García Falgueras et al., 2012; Meyza et al., 2009; 20 21 12 Rio-Alamos et al., 2019; Tapias-Espinosa et al., 2019; Table 3). Such developmental 22 23 13 alteration may be due to dysfunctional dopamine/GABA/glutamate interactions, and may 24 25 14 lead to a decreased cortical function accounting, at least in part, for the schizophrenia- 26 15 27 relevant and drug addiction-related phenotypic profile of the RHA strain (see Figure 1 28 16 and Figure 2). 29 30 31 17 32 33 34 18 3. A neurodevelopmental glutamatergic hypothesis 35 36 19 37 As we have seen in the previous sections several behavioral and endocrine phenotypes of 38 20 the RHA model emerge in the early postpubertal period or during young adulthood, and 39 40 21 such a developmental onset may be reminiscent of some schizophrenia-linked features. 41 42 22 The altered regulation in the expression of particular receptors, neurotrophic factors and 43 44 23 synaptic markers in the PFC and HC of RHA rats (e.g. Homer1, Nrg1, Syp, Bdnf, Grin2B, 45 24 46 Snap25, Drd1, Snapin,Vamp1), collectively resemble an immature/adolescent stage of 47 25 48 brain development in these rats, in keeping with the neurodevelopmental hypothesis of 49 26 schizophrenia. Several of these marker alterations have been related with 50 51 27 attentional/cognitive phenotypes and with schizophrenia, and the extended variations 52 53 28 observed are in agreement with the notion that alterations of synaptic networks are one 54 29 55 of the main pathophysiological underpinnings of schizophrenia (Elfving et al., 2019, and 56 references therein). 30 57 58 59 60 61 62 21 63 64 65 1 Due to the cys407* mutation in Grm2, the mGlu2 receptor is missing in RHA rats during 1 2 2 development and throughout their lifetime, which probably leads to adaptations in 5-HT2A 3 3 receptors, serotonergic transmission, and in other systems, such as the mesocorticolimbic 4 5 4 dopaminergic pathways. It is noteworthy that mGlu2 Receptor Knockout (mGlu2-KO) 6 7 5 mice exhibit a variety of phenotypes indicating enhanced vulnerability to drug addiction 8 9 6 and schizophrenia-relevant features (Morishima et al., 2005), including: (1) increased 10 11 7 susceptibility to develop locomotor sensitization and conditioned place preference upon 12 13 8 repeated cocaine administration, (2) augmented extracellular levels of dopamine and 14 9 15 glutamate in the NAcc following acute cocaine administration, (3) hyperactivity under 16 10 17 novelty/stressful conditions, (4) augmented hyperactivity following acute amphetamine, 18 11 (5) impaired spatial working memory (De Filippis et al., 2015; Hideshima et al., 2018; 19 20 12 Morishima et al., 2005), (6) some signs of decreased anxiety in an open-field-like test and 21 22 13 an active coping style (De Filippis et al., 2015; Hideshima et al., 2018; Morishima et al., 23 24 14 2005). These phenotypes of mGlu2-KO mice closely resemble the psychostimulant- 25 15 induced sensitization of locomotor activity, increased mesolimbic dopamine and 26 27 16 28 glutamate function following chronic treatment with psychostimulants, hyperactivity, 29 17 active coping style and cognitive phenotypic profiles observed in the RHA model (Giorgi 30 31 18 et al., 2019; Piras et al., 2010, 2014; Serra et al., 2018). Moreover, also regarding the 32 33 19 parallelism between mGlu2-KO mice and RHA rats, it is remarkable that the former 34 35 20 exhibit a reduced responsivity to the behavioral effects of psychotomimetic 5-HT2A 36 21 37 receptor agonists like 2,5-dimethoxy-4-iodoamphetamine (DOI) or lysergic acid 38 22 39 diethylamide (LSD) and the 5-HT2A receptor antagonist, clozapine. This is consistent 40 23 41 with the fact that the 5-HT2A/mGlu2 receptor complex is disrupted (Hideshima et al., 42 24 43 2018; Moreno et al., 2011), whereas the density of 5-HT2A receptors in the PFC, as 44 25 determined with the radiolabeled ligand [3H]ketanserin, is preserved (Hideshima et al., 45 26 46 2018; Moreno et al., 2011). Likewise, relative to RLA rats, the DOI-induced PPI 47 27 48 impairment and the clozapine antagonism of the dizocilpine-induced PPI impairment 49 28 50 (Oliveras et al., 2017) are reduced in RHA rats, although [3H]ketanserin binding in the 51 29 52 PFC is also preserved (Fomsgaard et al., 2018; Klein et al., 2014). Hence, it appears that 53 30 54 at least some of the adaptive changes due to the permanent absence of mGlu2 receptors 55 31 in RHA rats closely resemble those seen in the mGlu2-KO mice. Importantly, the reduced 56 32 effects of the 5-HT2A receptor agonists, DOI and LSD, and the 5-HT2A receptor 57 58 33 antagonist, clozapine, in both mGlu2-KO mice and RHA rats, are consistent with the 59 60 34 hypothesis that both receptors of the 5-HT2A/mGlu2 complex in the PFC interact to 61 62 22 63 64 65 1 mediate some antipsychotic and propsychotic drug effects, thus perhaps being involved 1 2 2 in some schizophrenia-relevant manifestations (Fribourg et al., 2011; González-Maeso 3 3 et al., 2008). 4 5 6 4 Considerable evidence indicates that the mGlu2 receptor plays an important role in 7 8 5 regulating the dopaminergic system both presynaptically and postsynaptically 9 10 6 (Morishima et al., 2005). Thus, pharmacological studies have shown that mGlu2 11 12 7 receptors inhibit pyramidal neurons postsynaptically in the PFC and presynaptically in 13 14 8 the NAcc (Morishima et al., 2005). Hence, the lack of mGlu2 receptors may result in a 15 9 reduced inhibition of pyramidal neurons in both the PFC and the NAcc, thereby leading 16 17 10 to an increased release of glutamate in the NAcc (Morishima et al., 2005) (Figure 1). It 18 19 11 may be postulated that the increased extracellular concentration of glutamate can 20 21 12 stimulate NMDA receptors at the presynaptic terminals of DA neurons in the NAcc, 22 23 13 inducing further increments in DA concentrations in the synaptic cleft and leading to a 24 25 14 stable enhancement of the functional tone of the mesolimbic DA system. This hypothesis 26 15 27 is consistent with the enhanced vulnerability to sensitization induced by drugs of abuse 28 16 or with the increased density of D1 receptors in the PFC and NAcc of RHA rats (Elfving 29 30 17 et al., 2019; Giorgi et al., 1994, 2007; Guitart-Masip et al., 2006). 31 32 33 18 The mGlu2 receptors are involved in LTD-related synaptic plasticity in the HC and the 34 35 19 AMY (Lucas et al., 2013), and also in synaptic pruning during adolescence (Selemon, 36 20 37 2013). Therefore, the disruption of the normal maturation of the HC (and perhaps other 38 21 limbic regions, such as the AMY), due to the lack of mGlu2 receptors in RHA rats 39 40 22 (Elfving et al., 2019; Fomsgaard et al., 2018; Klein et al., 2014), may also facilitate the 41 42 23 sensitization of DA systems to addictive substances. Accordingly, in the NVHL model, 43 44 24 the neonatal lesion of the ventral hippocampus prevents the normal maturation of the HC 45 25 and elicits a broad spectrum of schizophrenia-related phenomena that become apparent 46 47 26 48 in the postpubertal period, some of which are ameliorated by antipsychotics (e.g. Corda 49 27 et al., 2006; Tseng et al., 2009). Interestingly, among other schizophrenia- and addiction- 50 51 28 relevant features, the NVHL model shows, similar to RHA rats, enhanced locomotor and 52 53 29 DAergic sensitization following chronic administration of psychostimulants (Corda et al., 54 55 30 2006; Tseng et al., 2009). Another important parallelism with the RHA model is that in 56 31 the NVHL model the density of 5-HT2A receptors is elevated in the PFC (Mitazaki et 57 58 32 al., 2020; Fomsgaard et al., 2018; Klein et al., 2014), although mGlu2 receptors have not 59 60 33 been measured in NVHL rats. Hence, both the RHA and NVHL models appear to have 61 62 23 63 64 65 1 in common some alterations of dopamine and serotonin transmission that are likely 1 2 2 involved in certain schizophrenia-related features. 3 4 3 As postulated for the NVHL model, the anomalous hippocampal maturation in RHA rats 5 6 4 (linked to their deficit of mGlu2 receptors) would alter the normal regulation of GABA 7 8 5 interneurons by the mesocortical DA pathway in the PFC (Tseng et al., 2009, and 9 10 6 references therein). HC disruption in the NVHL model leads to post-pubertal anomalous 11 12 7 NMDA- and D1-mediated activation of prefrontal cortical pyramidal neurons and 13 14 8 GABAergic interneurons (Tseng et al., 2009, and references therein), which might be 15 9 related to the altered excitation/inhibition balance observed in NVHL rats (Tseng et al., 16 17 10 2009). Consistent with these findings from the NVHL model, RHA rats present a 18 19 11 decreased volume and task-induced activity of the HC and the PFC (Meyza et al., 2009; 20 21 12 Río-Álamos et al., 2019; Sallés et al., 2001; Tapias Espinosa et al., 2019), prefrontal 22 23 13 cortical increases of NMDA and D1 receptors (Elfving et al., 2019), and a reduced PPI- 24 25 14 induced activity of (PV+) GABAergic interneurons in the PFC (Tapias-Espinosa 2020), 26 15 27 all of which are compatible with an altered excitation/inhibition balance in the PFC. 28 29 16 Thus, early alterations of hippocampal development and synaptic processes in RHA rats, 30 31 17 driven by the lack of mGlu2 receptors, may affect the normal development of brain 32 33 18 regions and systems that mature later in adolescence, such as the PFC and its DA 34 35 19 /glutamate/GABA (and thus, inhibitory/excitatory) functional balance. It may be 36 20 37 proposed that the early disruption of the HC is crucial for the generation of the 38 21 frontocortical phenotypes observed in adult RHA rats (e.g., hypofrontality; Meyza et al., 39 40 22 2009; Río-Álamos et al., 2019; Tapias-Espinosa et al., 2019). This process bears 41 42 23 resemblance to what is considered to occur in the NVHL model (e.g. Corda et al., 2006; 43 44 24 Tseng et al., 2009), and further longitudinal/developmental studies are warranted to 45 25 establish whether this is indeed the case in the RHA model. 46 47 48 26 49 50 51 27 3.1. Summary and hypothetical scheme 52 53 28 54 Summarizing and simplifying, the main aspects of our neurodevelopmental glutamate- 55 29 based hypothesis, concerning the schizophrenia- and addiction-relevant anomalies that 56 57 30 the RHA model exhibits, can be formulated as follows (see Figure 2): 58 59 60 61 62 24 63 64 65 1 Glutamate-mediated synaptic plasticity is involved in synaptic pruning and dendritic 1 2 2 spine maturation during neurodevelopment. Therefore, the lack of mGlu2 receptors (due 3 3 to the cys407* mutation) in PFC, HC and STR of RHA rats, and thus the alterations of 4 5 4 the 5-HT2A/mGlu2 receptor complex function, could lead (or might be related) to a series 6 7 5 of associated neurodevelopmental processes, such as: 8 9 10 6 (i)- Alterations in prefrontal (and hippocampal) BDNF system, which shows functional 11 12 7 interactions with mGlu2 receptors, and may lead to altered plastic and synaptic 13 14 8 neurodevelopmental processes. 15 16 9 (ii)- Synaptic alterations at PSD, such as Homer1 and Nrg1, which are involved in 17 18 10 glutamatergic, dopaminergic and serotonergic signaling, and in the regulation of 19 20 11 excitatory/inhibitory neurotransmission. 21 22 23 12 (iii)- These altered levels of Homer1, Ngr1 and BDNF, that are known to be important 24 13 25 regulators of dendritic spine morphogenesis and density, are likely related to synaptic 26 14 alterations in the PFC of RHA rats. 27 28 29 15 (iv)- In fact, in the PFC of RHA rats there is up-regulation of some core presynaptic 30 31 16 markers of the SNARE complex, which regulates glutamate NMDA receptor-linked 32 33 17 processes. 34 35 18 36 (v)- Consistently, an increased density of immature (“thin”) dendritic spines (which are 37 19 known to express NMDA receptors) is observed in the PFC of RHA rats. 38 39 40 20 (vi)- There is an increased number of astrocytes in the PFC of RHA rats. Given their 41 42 21 important role in the maturation of excitatory synapses, such an increased number of 43 44 22 astrocytes is likely associated with the dendritic spine alterations in this rat strain. 45 23 46 Alterations in astrocyte regulation of glutamate release in the PFC, through activation of 47 24 their mGlu2/3 receptors, and thus altered NMDA receptor activation may contribute to 48 49 25 these anomalies in dendritic spines. 50 51 52 26 (vii)- There are alterations of NMDA receptor activation in the PFC, also linked to altered 53 27 GABA interneuron activity in the PFC of RHA rats, which in turn might be linked to 54 55 28 disrupted Nrg1/ErbB4 signaling in these GABA neurons. Such disruption of Nrg1/ErbB4 56 57 29 signaling may be involved in dendritic spine destabilization and glutamatergic 58 59 30 disfunction. 60 61 62 25 63 64 65 1 (viii)- GABA interneurons in the PFC receive dopaminergic innervation from the ventral 1 2 2 tegmental area (VTA) and express D1 and D2 receptors. D1 receptors are involved in 3 3 NMDA receptor trafficking to postsynaptic membranes. Both D1 and NMDA2B 4 5 4 receptors show increased density in PFC of RHA rats. 6 7 8 5 (ix)- Hence, there is likely an altered excitatory (glutamate-linked)/inhibitory (GABA- 9 10 6 linked) balance in the PFC of RHA rats, and impaired top down inhibitory control (Figure 11 12 7 1, Figure 2). 13 14 8 15 (xi)- Consistent with the above is the decreased function of PFC and HC in RHA rats, 16 9 likely related to a poor top down inhibitory control (Figure 1, Figure 2) and, specifically, 17 18 10 to their deficit of impulse control, as well as attentional, cognitive and social behavior 19 20 11 impairments. 21 22 23 12 (xii)- Such an impaired top down inhibitory control is likely related to the increased 24 13 25 mesolimbic dopaminergic functional tone in RHA rats, increased behavioral and 26 14 27 dopaminergic sensitivity to acute and chronic psychostimulants (and other drugs of 28 15 abuse), impaired sensorimotor gating (that initiates during adolescence), and behavioral 29 30 16 disinhibition (i.e. increased locomotor activity) that is already present at pre-puberty and 31 32 17 early puberty in the RHA model (Figure 1, Figure 2). 33 34 18 35 In sum, it is hypothesized that the lack of mGlu2 receptors (and thus the alteration of 5- 36 19 37 HT2A/mGlu2 receptor complex function) in RHA rats may underlie a cascade of 38 20 processes leading to neurodevelopmental alterations that finally shape a number of neural 39 40 21 and behavioral phenotypes that collectively resemble an immature/adolescent stage of 41 42 22 brain development in these rats. These traits are consistent with a neurodevelopmental 43 44 23 view of schizophrenia-relevant features and drug addiction-related phenomena. 45 46 24 47 48 49 25 50 4. Concluding remarks and perspectives 51 52 26 Genetically-derived rat models based on selective breeding for specific phenotypic 53 27 differences have received much less attention than genetically-engineered rodent models, 54 55 28 i.e. gene targeting approaches such as transgenic or knockout mice. These gene targeting 56 57 29 models constitute etiology-focused strategies (i.e. if a gene is manipulated and produces 58 59 30 consequences in a given phenotype, then the gene is considered to be one possible “cause” 60 61 62 26 63 64 65 1 underlying that trait). Notably, however, the etiological hypotheses are the main 1 2 2 constraints of these models. One of their limitations stems from their frequently applied 3 3 single-mechanism approach, which usually disregards many other possibly relevant 4 5 4 neurobiological, neurodevelopmental, genetic, epigenetic, and environmental factors or 6 7 5 processes that may be germane to the target phenotype/disease. This is especially true 8 9 6 when dealing with complex multifaceted, multicausal and neurodevelopmental polygenic 10 11 7 syndromes or traits, such as schizophrenia or its associated symptoms (e.g. Ayhan et al., 12 13 8 2016; Schizophrenia Working Group of the Psychiatric Genomics Consortium 2014; 14 9 15 Flint and Munafo 2014). A complementary and more ethologically oriented approach, 16 10 17 which can overcome these limitations of gene targeting approaches, would be to use top- 18 11 down “behavior-to-biology” models, such as animals selectively bred for their values in 19 20 12 a given quantitative phenotype (of which the Roman rats are an example). These 21 22 13 approaches, similarly to the strategy used by human “genome wide association studies” 23 24 14 (GWASs), rather than assuming a given pathophysiological mechanism (as do gene 25 15 targeting approaches) take advantage of the quantitative phenotypic (or trait) variation to 26 27 16 28 study its association with “normal” genotypic variation to find “candidate quantitative 29 17 genes”. One advantage of gene targeting approaches is the possibility of controlling for 30 31 18 genetic/epigenetic processes, since littermates can be used as controls. This is not possible 32 33 19 when using selectively bred strains, although (i) comparison of these strains with other 34 35 20 (as many as possible) standard laboratory strains, and (ii) systematic phenotypic 36 21 37 evaluation and comparison of sub-strains established at different locations, may mitigate 38 22 39 that problem of “controls”. For example, it is noteworthy that the main (avoidance, 40 23 41 emotional, cognitive, endocrine, addiction- and schizophrenia-related) traits/phenotypes 42 24 differentiating RHA vs RLA rats have been maintained across different laboratories 43 44 25 (Spain, Italy, Switzerland, Germany, France, England, USA; see Table S1). On the other 45 26 46 hand, compared with gene targeting models, studies based on the selective breeding for 47 27 48 particular phenotypes (or even stratification for quantitative phenotypes without carrying 49 28 out selective breeding) present the unique advantage of allowing to carry out quantitative 50 51 29 52 genetics (i.e. GWAS-like) studies, which in turn allow identification of multiple 53 30 quantitative trait genes in the same study (e.g. Baud et al., 2013, 2014a,b; see Table S1 54 55 31 for other quantitative genetic studies based on selectively bred rats). 56 57 32 58 Regarding the Roman rats, one such quantitative genetics study (in an approach similar 59 33 60 to GWASs) pioneered bringing glutamatergic neurotransmission to the scene in relation 61 62 27 63 64 65 1 to genetic differences between the RHA and RLA strains. Thus, using > 800 F2 rats 1 2 2 (hybrids of RHA and RLA strains), we reported a “quantitative trait locus” (QTL) in 3 3 chromosome 5 influencing two-way avoidance acquisition and other phenotypes related 4 5 4 to cognition (i.e. pavlovian aversive conditioning), locomotor activity, risk taking and 6 7 5 self-grooming (Fernandez-Teruel et al., 2002b). Further fine-mapping of this QTL 8 9 6 revealed that it contained only 9 genes (Johannesson et al., 2009), one of which is the 10 11 7 Mpdz (Multiple PDZ domain protein) gene, a member of the NMDA receptor signaling 12 13 8 complex that seems to be involved in control of AMPA receptor potentiation and synaptic 14 9 15 plasticity, and has also been associated with 5-HT2C and possibly GABA-B receptor 16 10 17 function. Mpdz is currently considered as a quantitative trait gene influencing alcohol 18 11 comsumption and withdrawal (e.g. Metten et al., 2014; Milner et al., 2015), and some 19 20 12 effects of opiates (Donaldson et al., 2016). Although no further characterization of the 21 22 13 Mpdz gene has been carried out in the Roman rat strains, this gene would deserve further 23 24 14 exploration, given that: (i) it appears to connect glutamate, serotonin and maybe GABA 25 15 activities, and (ii) RHA and RLA rats markedly differ in their sensitivity to, and 26 27 16 28 preference for ethanol and other abused drugs, and in the effects of NMDA receptor 29 17 antagonists. 30 31 32 18 The complexity of the genetic mechanisms associated with schizophrenia was in fact 33 34 19 highlighted by a recent metanalysis of GWAS studies carried out by the Psychiatric 35 20 Genomics Consortium (PGC), which identified 108 loci that contribute to risk for the 36 37 21 38 disorder. Studying 37,000 patients with schizophrenia and 113,000 healthy controls the 39 22 consortium identified 83 novel risk markers and replicated 25 existing markers, among 40 41 23 42 which genes involved in neurodevelopment, the immune and stress response, 43 24 glutamatergic neurotransmission, and DA D2 receptors stand out. It is interesting that, 44 25 45 particularly regarding neurodevelopmental aspects, glutamate and DA 46 26 47 neurotransmission, this study by the consortium shows striking coincidences with what 48 27 49 we have discussed about RHA (vs RLA) rats in the present article. 50 51 28 52 There is considerable consensus that in order to understand the neurogenetic bases of 53 29 schizophrenia we will need to work with models that take into account gene-environment 54 55 30 interactions. Thus, for instance, interactions between genetic risk and environmental 56 31 57 stressors or factors modulating experience-dependent plasticity –in interaction with 58 32 59 ontogeny- are generally thought to be of great importance in the development of the 60 33 disorder (e.g. Burrows and Hannan 2016; Laviola et al., 2009; Moran et al., 2016; 61 62 28 63 64 65 1 Nimgaonkar et al., 2017). In this regard, as mentioned earlier in this article, we have 1 2 2 reported genotype-environment effects of (stressful) isolation rearing and RHA genotype 3 3 on emotional, cognitive and attentional phenotypes (Oliveras et al., 2016; Sanchez- 4 5 4 González et al., 2019), as well as of neonatal handling and RHA genotype on emotional 6 7 5 responses, sensotimotor gating (PPI), cognitive flexibility, social behavior and 8 9 6 hippocampal volume (Río-Álamos et al., 2017b, 2019; Sampedro-Viana et al., 2021). 10 11 7 Ongoing studies are focused on exploring the genetic/epigenetic underpinings of some of 12 13 8 these genotype-environment interactions in the RHA vs RLA rats. 14 15 9 The RHA model constitutes the first genetically-based (selectively-bred) rat model of 16 17 10 schizophrenia-relevant features having a mutation that precludes the presence of mGlu2 18 19 11 receptors. This, as seen in the present review, may have relevant implications for the 20 21 12 research on the relationship between glutamate and 5-HT, GABA and DA transmission, 22 23 13 as well as for the neurodevelopmental effects related to mGlu2 receptors and their role in 24 25 14 schizophrenia- and addiction-related features. On the other hand, it is worth noting that, 26 15 27 relative to RHAs and other rat strains/stocks, RLA rats appear to be resistant to locomotor 28 16 and mesolimbic sensitization induced by chronic treatments with psychostimulants, 29 30 17 morphine or alcohol, while apparently exhibiting traits of good PFC- and HC-related 31 32 18 inhibitory control as well as of good attentional/cognitive traits and resistance to the 33 34 19 deleterious effects of isolation rearing. Altogether, these findings suggest that RLA rats 35 20 may represent a valid model of resistance to both substance abuse and developmentally- 36 37 21 38 induced schizophrenia-related phenotypes (Figure 1). 39 40 22 Turning back to the RHA model, it can be said that it presents reasonable face validity, 41 42 23 as shown by increased locomotor activity, decreased social behavior, impairments in 43 44 24 attention and cognitive processes, deficits induced by social isolation rearing, enhanced 45 25 46 sensitivity to (acute and chronic) psychostimulant effects and vulnerability to drug 47 26 48 sensitization and addiction. The predictive validity of the model also seems reasonable, 49 27 and relies in the observed differential (RHA vs RLA) effects of psychostimulants 50 51 28 52 (amphetamine, apomorphine, cocaine) and some antipsychotic (haloperidol, clozapine, 53 29 ziprasidone, aripiprazole, oxytocin) and propsychotic drugs (dizocilpine, DOI), observed 54 30 55 on PPI, dizocilpine-induced hyper-locomotion, or dizocilpine-impaired social interaction 56 31 57 preference. Other antipsychotic (and putative antipsychotic) drugs, other administration 58 32 59 regimes and other tasks, for instance, will be necessary to get further insight on the 60 33 predictive validity of the model. 61 62 29 63 64 65 1 The described alterations of the 5-HT2A/mGlu2 receptor complex and the 1 2 2 mesocorticolimbic dopaminergic characteristics, together with the aforementioned 3 3 changes in pre- and post-synaptic markers, dendritic spines, trophic factors, 5-HT and 4 5 4 NMDA receptors, and PFC and HC hypofunction in RHA rats (Figure 1-2), seem to 6 7 5 provide them some construct validity as a neurodevelopmental model of schizophrenia- 8 9 6 and drug addiction-related traits. In this regard, in order to explore further the involvement 10 11 7 of the mGlu2-related mutation in the neurobehavioral profile of RHA rats, it would be 12 13 8 interesting to study whether restoring the expression of mGlu2 receptors (using virally 14 9 15 mediated over-expression, for instance; see Hideshima et al., 2018) in the PFC and/or HC 16 10 17 could contribute to “normalize” some of their characteristic behavioral, neural and/or 18 11 pharmacological profiles. 19 20 21 12 The reviewed evidence strongly suggests a more immature state of the PFC (and probably 22 23 13 the HC) in the RHA rats, which may underlie their schizophrenia- and addiction-related 24 25 14 neurobiological traits. Current and future studies of our group are aimed at performing a 26 15 27 transcriptomic analysis and look for enrichment of gene pathways related to 28 16 neurodevelopment (i.e. differential expression of functional gene modules differentially 29 30 17 regulated during childhood and early adolescence) in RHA rats. Only a few studies have 31 32 18 previously looked at gene expression profiles in these rat strains (Sabariego et al., 2011, 33 34 19 2013). These were though microarray based studies, that do not have the same coverage 35 20 36 as transcriptomics approaches. Still, among the differential expressed genes, 14 up- 37 21 38 regulated and 24 down-regulated in RLA vs. RHA rats, they found enrichment in 39 22 processes related to neurodevelopment and function (Sabariego et al., 2011). In the 40 41 23 second study, they found, after exposing both strains to a frustrative experience involving 42 43 24 reward downshift, differential gene expression in the hippocampus of genes involved in 44 45 25 cellular growth and proliferation and synaptic function (Sabariego et al., 2013). More 46 26 47 studies are needed exploring more in detail the differences in gene expression profile 48 27 between these two strains in PFC areas and relate them to neurodevelopment and 49 50 28 executive function maturation. Based on these previous studies we expect this to be quite 51 52 29 extensive. 53 54 55 30 56 57 31 58 59 60 61 62 30 63 64 65 1 Acknowledgements.- The authors and part of the work reviewed herein are supported, 1 2 2 or have received support from grants PID2020-114697GB-I00, PSI2017-82257-P, 3 4 3 2017SGR-1586 and “ICREA-Academia 2013” (A.F-T., A.T.), PSI2017-87340-P (C.T), 5 4 “ARS, L.R. 7/2007, Ref. 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Neurosci. 33, 41 27 19295-19303. 33/49/19295 [pii];10.1523/JNEUROSCI.2090-13.2013 [doi] 42 43 28 Zeier, H., Bättig, K., Driscoll, P., 1978. Acquisition of DRL-20 behavior in male and 44 29 45 female, Roman high- and low-avoidance rats. Physiol. Behav. 20, 791–793. 46 30 https://doi.org/10.1016/0031-9384(78)90307-4 47 48 31 49 Zuckerman, M., 1996. The psychobiological model for impulsive unsocialized sensation 32 seeking: A comparative approach. Neuropsychobiology 34, 125–129. 50 51 33 https://doi.org/10.1159/000119303 52 53 34 54 55 35 56 57 58 59 60 61 62 72 63 64 65 A Figure 1 RLA rats BEHAVIORAL INHIBITION -Resistance to psychostimulant sensitization and to drug addiction -Normality regarding schizophrenia-relevant traits: good PPI and LI, good spatial and working memory, good cognitive flexibility, normal social behavior, resistant to MK801-induced impairment of social preference and hyperactivity, impulse control. PFC INHIBITORY CONTROL AMY -Normal mGlu2 receptor levels AFFECTIVE STATE (normal glutamatergic tonus) -Hyperfunctional NoGo Go -Enhanced fear learning HC - NAcc + Incentive INHIBITORY CONTROL -Hyperfunctional D2 D1 -Anxiety -Behavioral inhibition VTA RHA rats BEHAVIORAL DISINHIBITION -Impulsivity / Sensation-novelty seeking B PFC -Schizophrenia-like positive symptoms, negative symptoms (asociality) and attentional/cognitive INHIBITORY CONTROL (DECREASED) impairments (e.g. PPI, LI, starle habituation, working memory) -Hypofunctional state/ Hypofrontality -Enhanced NMDA antagonist-induced hyperactivity and impairment -Decreased mGlu2 receptors of social interaction preference (disrupted glutamatergic transmission) -Enhanced psychostimulant sensitization -Increased 5-HT2A receptors -Vulnerability to drug abuse/addiction (enhanced impulsivity) -Increased BDNF -Increased Homer 1 -Increased Neuregulin 1 AMY -Altered pre-synaptic markers AFFECTIVE STATE -Increased NMDA2B receptors -Increased D1 receptors NoGo Go -Hypofunctional -Decreased fear learning -Increased astroglia number -Increased density of immature (“thin”) pyramidal dendritic spines -Decreased activity of GABA interneurons -Disrupted excitation/inhibition balance - NAcc + D2 Incentive D1 HC VTA INHIBITORY CONTROL (DECREASED) -Hypofunctional state -Decreased mGlu2 receptors -Decreased anxiety -Behavioral disinhibition under conflict • Legend to Figure 1.- Simplified model of the functions of the mesocorticolimbic dopaminergic circuit and its modulation by limbic and frontocortical areas in relation to their differential involvement in behavioural inhibition/disinhibition, impulsivity, schizophrenia-like features, and drug seeking/addiction in RHA and RLA rats. In this schematic diagram the arrow thickness and character size represent the intensity of the functional tone or the receptor (or marker) density of the corresponding brain area or neural circuit, respectively. The lower neuronal activity and volume of the mPFC, the HC, and the AMY, the increased density of 5-HT2AR and the absence of mGlu2R, together with the alterations of BDNF, Homer1, Neuregulin 1, NMDA2B and D1 receptors, and pre- synaptic markers in RHA vs. RLA rats, is consistent with the possibility of a hyper- functional glutamatergic cortical system that would in turn lead to an increased functional tone of the mesolimbic dopaminergic system and a decreased functional tone of the meso-cortical dopaminergic system in RHA rats. These alterations of synaptic markers, trophic factors and GABA interneuron function in the PFC are also consistent with the increased density of immature (“thin”) pyramidal dendritic spines and astroglia in RHA rats, which collectively characterize an immature PFC (and, likely, HC), and thus an altered excitation/inhibition balance and a disrupted top down inhibitory control. Collectivelly, the lowered function of the PFC, the HC, and the AMY, along with the increased functional tone of the mesolimbic dopaminergic system of RHA rats favour behavioral disinhibition, impulsive actions/responses, attentional/cognitive deficits and vulnerability to drug addiction. Abreviations: PFC, prefrontal cortex; HC, hippocampus; AMY, amygdala; NAcc, nucleus accumbens; VTA, ventral tegmental area; mGlu2R, metabotropic glutamate type 2 receptors; 5- HT2AR, serotonin type 2A receptors; D2, dopamine type 2 receptors; D1, dopamine type 1 receptors; PPI, prepulse inhibition; LI, latent inhibition; NMDA, N-metyl-D-aspartate receptor; BDNF, brain-derived neurotrophic factor; GABA, gamma aminobutyric acid (see text). PFC Figure 2 MESOLIMBIC Click here to access/download;Figur -Reduced mGluR2 DAergic SYSTEM -Altered BDNF system HC -Reduced mGluR2 -Increased Homer1 & Nrg1 -Reduced mGluR2 -Increased D1 and decreased D2 -Increased SNARE complex markers -Altered BDNF system receptors -Altered NMDA receptor activation MOLECULAR -Altered GABA interneuron activity IMPAIRED TOP-DOWN PROCESSES & Nrg1/ErbB4 signalling -Increased 5-HT2A receptors INHIBITORY CONTROL -Increased density of D1 and NMDA2B receptors -Altered neuronal plasticity (dendritic Altered Increased spines) and synaptic Decreased HC mesolimbic excitatory/inhibitory development balance neuronal density DAergic funcional -Increased astrocytes tone CELLULAR PROCESSES Impaired PFC, HC and mesocorticolimbic function -Deficit in impulse control Attentional Reward & Social -Increased & Cognitive Drug impairment locomotor impairment seeking behavior Disinhibition BEHAVIOR Legend to Figure 2.- Main molecular, cellular and behavioral alterations in the RHA rat model of schizophrenia- and drug addiction-relevant features. Green arrows indicate “interaction”. Red arrows indicate “alteration” or“impairment”. See text for abbreviations in Fig. 1 and text. Table 1 Table 1.- Main behavioral phenotypes related to schizophrenia, addiction and impulsivity in treatment-naïve RHA rats. Related Behavioural phenotype Effects of RHA genotype (vs RLA, Wistar or Wistar--derived, Representative references pathology Sprague Dawley, HS rats, and other strains/stocks) Schizophrenia Locomotor activity (baseline) * Higher locomotor activity in treatment-naïve RHA rats in various Escorihuela et al., 1997, 1999; Estanislau et al., novelty-based tests (vs. RLA and outbred HS rats) 2013; Fernández-Teruel et al., 1991a, 1992a, 1993; Gentsch et al., 1981, 1991; Gimenez-Llort et al., 2005; Tapias-Espinosa et al., 2018; Oliveras et al., 2016, 2017; Driscoll et al., 2009 Latent Inhibition (LI) RHA rats have impaired latent inhibition, in the two-way active Fernández-Teruel et al., 2006; Esnal et al., 2016 avoidance and fear-potentiated startle paradigms, relative to Sprague- Dawley and RLA rats Prepulse inhibition (PPI) * RHA rats have impaired PPI compared to RLA and genetically- Del Río et al., 2014; Oliveras et al., 2015; 2016; heterogeneous (outbred) HS rats Río-Álamos et al., 2015, 2017a-b, 2019; Tapias- Espinosa et al., 2018, 2019 Habituation of acoustic startle RHA rats show decreased startle habituation compared with RLAs Aguilar et al., 2000; Rio-Alamos et al., 2015 response * Maternal behavior RLA mother rats are more protective of their litters than RHA mothers Driscoll et al., 1979, 1991; Del Río et al., 2014 (nursing/nesting) Social preference (drug-naive) * Impaired social preference (SP) of the RHA rats relative to RLA and Sampedro-Viana et al. (2021); Lavín 2019; outbred HS rats (RHA, 50 % SP; RLA, 70 % SP; HS, 70%) Torrecilla 2018 Table 1 (continued) Spatial reference RHA rats show impaired spatial reference memory relative to RLA Aguilar et al., 2002a; Driscoll et al., 1995; learning/memory in the Morris and outbred HS rats Escorihuela et al., 1995b; Martínez-Membrives water maze et al., 2015; Oliveras et al., 2016; Río-Álamos et al., 2019 Spatial working memory in the RHA rats show impaired working memory compared with RLA and Aguilar et al., 2002a; Oliveras et al., 2015, 2016; Morris water maze outbred HS rats Río-Álamos et al., 2019 Reversal place learning RHA rats show impaired cognitive flexibility (i.e. impaired Río-Álamos et al., 2019, Escorihuela et al., (cognitive flexibility) in the performance in the reversal place task) relative to RLA rats 1995b Morris water maze Non-spatial and spatial RHA rats are impaired in these tasks relative to RLA rats and to Guenaire et al., 1986; Guenaire and Delacour reference and working memory control (Wistar-derived) RCA rats 1985; Willig et al., 1991a-b, 1992 (delayed alternation, radial maze, novel object discrimination) Efficiency of hexagonal tunnel RHA rats explore the tunnel maze less efficiently than do RLA rats and Duetsch and Bättig, 1977; Driscoll and Bättig maze patrolling/exploration show impaired learning of most of the configurations of the Hebb- 1982; Nil and Bättig, 1981 and Hebb-Williams water maze Williams maze learning * Context-conditioned RHA rats exhibit reduced context (pavlovian)-conditioned suppression Guenaire et al., 1986; Escorihuela et al., 1997; suppression of drinking or and decreased context-and cue-conditioned freezing (compared with Fernandez-Teruel et al., 1998; Imada 1972; activity, and context- and cue- RLA and outbred HS rats) Lopez-Aumatell et al., 2009a conditioned freezing * Table 1 (continued) Addiction, novelty/reward- seeking Novelty-induced locomotion * Increased in RHA rats relative to RLA and outbred HS rats Diaz-Moran et al., 2012, 2013; Escorihuela et al., 1997, 1999; Estanislau et al., 2013; Fernandez-Teruel et al., 1991a-b, 1992a-b; Gentsch et al., 1981; Tapias-Espinosa et al., 2018 Sensation/novelty seeking * Increased in RHA relative to RLA and outbred HS rats Estanislau et al., 2013; Fernández-Teruel et al., 1992b, 1997; Pisula, 2003; Tournier et al., 2013 Preference for natural rewards Increased in RHA relative to RLA rats Giorgi et al., 2019; Sanna et al., 2014a, 2017, 2019 Drug-seeking and operant Increased in RHA vs. RLA rats in both the two-bottle free choice Corda et al., 2014; Dimiziani et al., 2019; behavior for intravenous drug (ethanol) procedure and operant intravenous self-administration Fattore et al., 2009; Fernández-Teruel et al., self-administration (cocaine) 2002a; Manzo et al., 2012, 2014a-b, 2015; Razafimanalina et al., 1996 Impulsivity 5-choice serial reaction time RHA rats exhibit increased impulsive (i.e. premature) responses Moreno et al., 2010; Klein et al., 2014; Merchan task (5-CSRTT) relative to RLA rats et al., 2019; Bellés et al., 2021 Delay discounting operant task Enhanced impulsivity of RHA rats in the delay-discounting task, Moreno et al., 2010 compared to RLA rats Table 1 (continued) Scheduled-induced polydipsia Increased impulsivity (i.e. increased amount of water drunk) in RHA Moreno and Flores 2012; Moreno et al., 2010; relative to RLA rats Merchán et al., 2019 Unpredictable instrumental Increased impulsivity in RHA relative to RLA rats Coppens et al., 2012, 2013 conditioning Learning an instrumental DRL20 Impaired learning, due to deficient inhibition of irrelevant responses Zeier et al., 1978 task * (i.e. to increased impulsivity), in RHA (vs. RLA rats) *, indicates that these studies (or some of them) used females or males and females; otherwise the studies were carried out with males. See abbreviations Table 2 Table 2.- Main psycho- and neuro-pharmacological phenotypes related to schizophrenia and addiction in RHA rats. Related pathology Psychopharmacological Effects of RHA genotype (vs RLA and, in some cases, Sprague Main references phenotype Dawley or outbred HS rats) Related to schizophrenia & drug addiction Apomorphine-induced More intense stereotypies in RHA than RLA rats Driscoll et al., 1985; Gimenez-Llort et stereotypies al., 2005 Locomotor activity or Higher locomotor activity or stereotypies in RHA than RLA rats Corda et al., 2005 Driscoll et al., 1986; stereotypies after acute Haney et al., 1994; Lecca et al., 2004. amphetamine or cocaine See reviews by Giorgi et al., 2007, 2019 Chronic amphetamine- More intense locomotor sensitization Corda et al., 2005; reviewed by Giorgi et induced locomotor In RHA rats than in RLA and Sprague Dawley rats al., 2007; Guitart-Masip et al., 2008a; sensitization Tournier et al., 2013 Locomotor activity after Higher locomotor activity in RHA than RLA rats Giorgi et al., 1997, 2005a, 2007; Lecca acute cocaine et al., 2004 Chronic cocaine-induced More intense sensitization in RHA than RLA rats Giorgi et al., 2005a, 2007 locomotor sensitization Locomotor activity after Higher locomotor activity in RHA than RLA rats Piras et al., 2003; Lecca et al., 2004 acute morphine Chronic morphine-induced More intense locomotor sensitization Piras et al., 2003; Giorgi et al 2007 locomotor sensitization in RHA than RLA rats Table 2 (continued) Haloperidol-induced Less intense hypoactivity induced by acute haloperidol in RHA Oliveras et al., 2017 hypoactivity than RLA rats Haloperidol effect on PPI RHA (but not RLA) rats acutely treated with haloperidol improved Oliveras et al., 2017 PPI performance Apomorphine effect on PPI RHA (but not RLA) rats acutely treated with apomorphine show Oliveras et al., 2017 impaired PPI Oxytocin effect on PPI RHA (but not RLA) rats acutely treated with oxytocin improved Tapias-Espinosa 2020; Tapias-Espinosa PPI performance by 18 % compared to the respective vehicle- et al., 2021 treated group (outbred HS rats were also included for comparison) Dizocilpine-induced increase Acute dizocilpine (dose-dependently) enhances locomotor Oliveras et al., 2017; of locomotor activity and activity more markedly in RHA rats than in RLA rats. Acute Torrecilla 2018 impairment of PPI dizocilpine impairs PPI to a similar extent in RHA and RLA rats Clozapine, aripiprazole and Clozapine, aripiprazole and ziprasidone attenuate dizocilpine- Oliveras et al., 2017; ziprasidone effects on induced hyperactivity more effectively in RHA than in RLA rats Lavín 2019 dizocilpine-induced locomotor hyperactivity Oxytocin effect on Moderate attenuation of dizocilpine (0.15 mg/kg)-induced Ancil-Gascón 2020 dizocilpine-impaired social impairment of social preference in RHA rats treated with oxytocin preference 0.04 and 0.2 mg/kg. No effect in RLA rats Table 2 (continued) Oxytocin effect on Moderate attenuation of dizocilpine (0.15 mg/kg)-induced Ancil-Gascón 2020; dizocilpine-induced locomotor hyperactivity in RHA rats treated with oxytocin 0.04 locomotor hyperactivity and 0.2 mg/kg. No significant effect in RLA rats Dizocilpine-impaired social A dose-related reduction of social preference in dizocilpine- Torrecilla 2018; Lavín 2019 preference treated RHA rats (> 60% reduction with the highest dose, 0.2 mg/kg) relative to the vehicle-treated group (no effect on social preference in RLA rats) Clozapine, ziprasidone and Attenuation (clozapine) or reversal (ziprasidone, aripiprazole) of Lavín 2019 aripiprazole effects on dizocilpine (0.15 mg/kg)-induced impairment of social preference dizocilpine-induced in RHA rats. No effect in RLA rats impairment of social preference Table 2 (continued) Related to addiction, reward seeking & dopaminergic mesolimbic involvement Psychostimulant Increased in RHA relative to RLA rats Giorgi et al. 2005b, 2007, 2019; Lecca et (amphetamine, cocaine)- (NAcc core) al., 2004 sensitized mesolimbic dopamine efflux Amphetamine (AMPH)- Enhanced AMPH-induced DA release in striatum, which Bellés et al., 2021 induced DA release in correlates with impulsive behavior, in RHA relative to RLA rats striatum (dorsal and ventral) Morphine-sensitized Increased in RHA relative to RLA rats Lecca et al., 2004; Giorgi et al., 2007 mesolimbic dopamine efflux (NAcc core) Chronic ethanol Both increased in RHA relative to RLA rats Corda et al., 2014 drinking/preference and chronic ethanol-induced accumbal dopamine efflux Sexual motivation and sexual Increased sexual motivation and sexual activity in RHA relative to Sanna et al., 2013, 2014a,b; 2015 activity, and RLA and Sprague Dawley rats, and increased dopamine efflux in mesocorticolimbic NAcc shell and mPFC during sexual activity in the former strain dopaminergic function Table 2 (continued) Apomorphine and haloperidol effects on sexual Apomorphine-induced facilitation and Sanna et al., 2014b activity haloperidol-induced impairment of copulatory behaviour were more robust in RLA than RHA rats See abbreviations in the text. Table 3 Table 3.- Main neuroanatomical, functional and molecular phenotypes related to schizophrenia in RHA rats. Neurobiological RHA vs. RLA rats Main references Phenotype Neuroanatomical and functional schizophrenia- relevant phenotypes of RHA rats: comparison with RLA rats Prefrontal cortex (PFC) Decreased volume and neuronal activity (c-fos), and Meyza et al., 2009; Río- Álamos et al., increased density of pyramidal dendritic “thin” 2019; Tapias- Espinosa et al., 2019; (immature) spines and astroglia number in RHA rats Sánchez-González et al., 2019, 2021 Nucleus Accumbens (NAcc) No difference in volume between RHA and RLA rats Giorgi et al., 2007; Río- Álamos et al., 2017b, 2019; Tapias- Espinosa et al., 2019 Hippocampus (HPC) Decreased volume, neuronal density and function (c- Garcia-Falgueras et al., 2012; Meyza et fos) in RHA rats al., 2009; Río-Álamos et al., 2017b, 2019; Sallés et al., 2001; Tapias- Espinosa et al., 2019; Sánchez- González et al., 2019 Amygdala (AMY) Decreased volume, neuronal density and function (c- Gomez et al., 2009c; Meyza et al., fos) in RHA rats 2009; Río- Álamos et al., 2017b, 2019; Tapias-Espinosa et al., 2019 Striatum volume No between-strain difference Río-Álamos et al., 2017; Tapias- Espinosa et al., 2019; Sánchez- González et al., 2019 Table 3 (continued) Anterior Cingulate volume No between-strain difference Río-Álamos et al., 2019; Tapias- Espinosa et al., 2019 Volume of lateral ventricles Much larger (2-fold) in RHA rats Río-Álamos et al., 2017b, 2019 Activation of parvalbumin (PV)- RHA rats exhibit an approximately 60% Tapias-Espinosa 2020 labelled GABA interneurons in reduced activation (measured by c-fos) of GABA (PV- prefrontal cortex following a PPI labelled) interneurons relative to RLA rats session Neurochemical/molecular phenotypes Dopamine (DA) Increased mesolimbic functional dopaminergic tone Giorgi et al., 2007, 2019; Tournier et in RHA rats al., 2013 Dopamine D1 receptors Increased density in limbic areas and increased Giorgi et al., 1994, Guitart-Masip et mRNA expression in PFC of RHA rats al., 2006; Elfving et al., 2019 Dopamine D2 receptors Decreased density in limbic areas in RHA rats Guitart-Masip et al., 2006; Tournier et al., 2013 Dopamine D3 receptors in NAcc Increased in RHA rats Guitart-Masip et al., 2006 Dopamine D3 receptors in Calleja Decreased in RHA rats Guitart-Masip et al., 2006 Islands Noradrenaline (NA) Increased NA levels and release in the PFC of RHA Sanna et al., 2017 rats Table 3 (continued) Serotonin (5-HT) Increased levels in the cortex (after MAO inhibition) Driscoll et al., 1980; Giorgi et al., in RHA rats. Increased release in PFC of RHA rats 2003b 5-HT receptors Increased fronto-cortical [3H]-paroxetine and [3H]- Charnay et al., 1995; Foomsgard et al., citalopram receptor binding in RHA rats. 2018; Giorgi et al., 2003b; Klein et al., Increased 5-HT2A receptor density in PFC of RHA 2014 rats mGlu2 receptors Dramatic reduction in PFC, HC and striatum of RHA Elfving et al., 2019; Kein et al., 2014; rats (see Wood et al., 2017) NMDA receptors Increased NMDA2B receptors in PFC of RHA rats Elfving et al., 2019 BDNF Increased expression in PFC of RHA rats Elfving et al., 2019; Sanna et al., 2019 Neuroregulin 1 Increased expression in PFC and increased protein Elfving et al., 2019 levels in HC of RHA rats Homer1 Increased expression in PFC of RHA rats Elfving et al., 2019 Pre-synaptic markers Altered SNARE complex proteins in PFC and HC of Elfving et al., 2019 RHA vs RLA rats See abbreviations in text. Supplementary Table 1 (continued) Table S1 Supplementary Table 1 (S1).- Main contributions from different groups working with the Roman rat lines/strains Country/City/Main Investigator/s & Main findings (or research lines) Main references Birmingham, UK / Broadhurst, Fulker, Hewitt, Wilcock Fulker et al., 1972; Hewitt and Fulker 1983; Hewitt et al., 1981 Wilcock and Broadhurst 1967; Wilcock and Fulker 1973; Wilcock (i)- 1st diallel cross of 8 rat strains (RLA, RHA and RCA, MR and MNR, TMB and TMD, et al., 1981) and WAG control strain), and a triple cross design including wild-type live-trapped rats. First genetic evidence to support the notion that two main (genetically-driven) processes are involved in the TWAA task, an initial dominant tendency to freeze (i.e. due to Pavlovian conditioned fear), which runs against escaping/avoiding the unconditioned stimulus (i.e. electric shock-), and a tendency that comes to play a role later in the process of acquisition, which favors the appearance of active crossings (escapes/avoidances) to the opposite compartment (ii)- Pioneers in showing that GABA production was related to two-way avoidance Buxton et al., 1976; Rick et al., 1971; Shephard et al., 1982, acquisition and exploratory activity in the open-field test, in studying the relationship 1984, 1985 between anxiety in a hyponeophagia test and brain levels of benzodiazepine receptors, and the genetic architecture of both hyponeophagia and the anxiolytic effects of diazepam in rats, using the RHA, RLA and RCA rat lines and 15 other rat crosses, as well as undertaking the first inter-rat line study on cholinergic transmission London, UK / Imada Imada 1972 First demonstration that RLA rats are more sensitive to classical aversive conditioning than are RHA, MNR and MR rats, i.e. the former showed the highest signs of fear-mediated (shock-induced) behavioral suppression of water drinking Supplementary Table 1 (continued) Thunder Bay, Canada / Satinder Satinder and Sterling 1983; Satinder and Wooldridge 1986 Satinder 1971, 1972, 1975, 1976b, 1981 (i)- Studies on the genetic-dependent and ontogenetic effects of amphetamine, ethanol, caffeine and morphine on emotionality and avoidance behavior, comparing the Satinder 1977 RLA/Lu, RHA/Lu, RCA/Lu with MNR/Har/Lu and MR/Har/Lu strains. Proposal of an U-inverted relationship between the degree of arousal and performance (ii)-First demonstration, in ethological predator tests, that RLA rats were among the Satinder 1976a most anxious of those five groups of rats when subjected to the presence of a cat, a rabbit or an empty box Zürich, Basel, Lausanne and Geneva, Switzerland / Driscoll, Bättig, Steimer, Gentsch, Lipp; Driscoll and Bättig 1979, 1982; Driscoll et al., 1979, 1991; also in collaboration with Tucson, AZ, USA/ Overstreet, and Bagneux, France/ Scatton, Duetsch and Bättig 1977; Gentsch et al., 1981a, 1982, 1988, Dedek 1991 (i)- First comprehensive evidence that RLA rats are more anxious/fearful and sensitive to stress than RHA rats are: The former ambulated (explored) less, defecated more and showed higher stress-induced corticosterone, ACTH and prolactin responses in open-field-like tests and novelty situations. RLA dams showed a more protective nursing behavior (ii)- First demonstration of cognitive impairment and impulsive traits in RHA, vs RLA, rats. Bättig and Schlatter 1978, 1979; Bättig et al., 1976; Nil and RHA rats were less capable of learning a DRL20 operant task (which requires inhibition Bättig 1981; Schlatter and Bättig 1979, 1981; Zeier et al., 1978 of irrelevant/impulsive behavior) and, related to this impulsive profile, they also showed reduced efficiency in non-spatial and spatial maze learning Supplementary Table 1 (continued) (iii)- Between-line differences in central serotoninergic, cholinergic, noradrenergic Charnay et al., 1995; D’Angio et al., 1988; Driscoll and Stübi, and dopaminergic systems, including studies on the differential effects of stressful 1985; Driscoll et al., 1980, 1983, 1985, 1990, 1995; Gentsch et environmental stimuli on mesocortical and mesoaccumbens dopaminergic neurons. al.; 1981b, 1983; Martin et al., 1981, 1982; Overstreet 1995; Determination of differences in the density of brain imipramine, paroxetine and diazepam Overstreet et al., 1981; Scatton et al., 1988 receptor binding sites, in line with findings that imipramine diazepam and pentobarbital differentially affected tunnel maze exploration and anxiety-related behavior in both rat lines (iv) Differential responses to behavioral and stereotypic responses induced by amphetamine Driscoll 1986; Driscoll and Bättig, 1982; Driscoll et al., 1985, and apomorphine, as well as both a higher turnover rate of striatal dopamine and alcohol 1986, 1990 (see also Durcan et al., 1984, Brewster 1969, and preference in RHA rats Drewek and Broadhurst, 1979 ) (v)- The size of hippocampal mossy fibers is negatively related to TWAA acquisition Lipp et al., 1984, 1988, 1989 in the Roman rats and in mice (vi)- Studies on differential coping styles of the RHA and RLA lines, as well as differential Boersma et al., 2009; Coppens et al., 2012, 2013; Steimer and endocrine responses to stress and their neural modulation, and central dopaminergic Driscoll 2003, 2005; Steimer et al., 1997a-b, 2007; Walker et al., mechanisms involved in the impulsivity profile and sensitivity to drugs of abuse in both lines 1989, 1992; Aubry et al., 1995; Charnay et al., 1995; Dimiziani et al., 2019; Tournier et al., 2013, 2018 Halifax, Canada / Henke Henke 1988a,b First in reporting that a specific type of activity in the central amygdala is associated with emotional reactivity and increased stress-induced stomach pathology. This type of activity was only observed in RLA rats and in (other) Wistar rats selected for their high emotional profiles Groningen, The Netherlands / Koolhaas Meerlo et al., 1997; Roozendal et al., 1992, 1993; Wiersma et al., 1997, 1998 Supplementary Table 1 (continued) (i)- Studies on the function of central amygdala (CeA), its modulation by CRF, vasopressin or oxytocin administration, and changes in behavioral (coping) and physiological (i.e. heart rate) stress- and fear-related responses: regulation of fear and stress responses by CeA was more important in the RLA rats (ii)- Differential insulin resistance, metabolism and obesity in the Roman rat lines were Boersma et al., 2009, 2011a,b, 2012; Evers et al., 2017 measured, relating these processes with the rats’ coping style and central dopaminergic function, and comparing them with the “proactive” and “passive”, Wild-Type Groningen rats Paris, France / Delacour, Guenaire Guenaire and Delacour, 1985; Guenaire et al., 1986; Willig et al., 1991a-b, 1992 (i)- Compared with their RLA and RCA rat lines, RHA rats were impaired in non-spatial working memory and spatial learning/memory (ii)- Intracerebroventricular administration of p-octopamine, a trace amine reported Becú-Villalobos et al., 1992; Coulon et al., 1989; David and to reverse some stress- hormonal responses and the context-conditioned suppression Delacour, 1980; David et al., 1982; Delacour et al., 1983; of locomotor activity, improved TWAA acquisition in RLA rats to the level of untreated RHA Delacour and Guenaire, 1983; Ennaceur et al., 1986; Guenaire rats. Hippocampal lesions also markedly improved TWAA acquisition in RLA rats and Delacour, 1983 Bordeaux, France / Mormede Castanon and Mormede 1994; Castanon et al., 1992, 1994, 1995; Kulikov et al., 1995; Sandi et al., 1991 (i)- Characterization of immunological, behavioral and neuroendocrine stress- and anxiety-related responses in Roman rats derived from the Roman/Verh lines, and analysis of the genetic association among some of these traits, as well as in differences in the selection trait, i.e. two-way active avoidance behavior. Demonstration of a genetic association between TWAA acquisition and prolactin responses to stress (ii)- RHA vs. RLA differences in preference for alcohol, saccharin, and quinine, as well as in Haney et al., 1994; Razafimanalina et al., 1996 sensitivity to cocaine effects: their modulation by sex and gonadal hormones Supplementary Table 1 (continued) Newark, DE, USA / Siegel Siegel 1997; Siegel and Driscoll, 1996; Siegel et al., 1993, 1996 (see also Saxton et al., 1987a,b) RHA rats are sensation/novelty seeker rats and, similar to what had been observed in novelty seeker cats and humans, RHA rats (compared with RLA and Wistar control rats) are cortical-evoked-potential augmenters Warsaw, Poland / Pisula, Meyza Pisula 2003; Pisula and Osinski, 2000 (i)- Using novel testing procedures, RHA rats showed much more novelty seeking behavior than RLA rats did (ii)- Medial prefrontal cortex, hippocampus, and basolateral/central amygdala were Meyza et al., 2009 more active (measured by cFos expression) in RLA than RHA rats under stressful, spatial novelty/conflict conditions Mainz and Magdeburg, Germany / Schwegler, Yilmazer-Hanke, Seidel Schwegler et al., 1997; Yilmazer-Hanke et al., 2002, 2016 (i)-Studies of differences in the amygdala and associations with fear- and anxiety-related responses provides evidence that the amygdala of RLA rats is more functional than that of their RHA counterparts (ii)- The pineals of RHA rats are twice as active in melatonin production than those Seidel et al., 1990 (see also Requintina et al., 1994) of RLA rats, and the pineal gland is also larger in RHA rats, also exhibiting an increased density of pineal synaptic ribbons Cagliari, Italy / Giorgi, Corda, Quartu, Serra, Sanna Corda et al., 1997, 2005, 2014; Fattore et al., 2009; Giorgi et al., 1994, 1997, 2005a-b, 2007, 2015; Lecca et al., 2004; Piras et al., 2003; Rosas et al., 2018 Supplementary Table 1 (continued) (i)- First demonstration that RHA rats are more sensitive to the acute and chronic (i.e. sensitization) effects of drugs of abuse, are more vulnerable to drug addiction, and have a more functional mesolimbic dopaminergic system (ii)- RHA rats display higher sexual motivation and sexual activity than do RLA and SD rats. Sanna et al., 2013, 2014a,b; 2015, 2017, 2019 (see also Melis et Sexual activity induces rat line-dependent neural activation in limbic brain areas involved al., 2019) in motivation and reward, leading to changes in synaptic plasticity (as measured by c-Fos, DFosB, BDNF, its receptor trkB, and Arc) with sexual experience acquisition, thus showing that these synaptic changes depend on the animals’ genotype/phenotype (iii)- Mesocortical dopamine release/function is dissociated from fear-related and Giorgi et al., 2003a,b (see also Piras et al., 2010, 2014) coping behavior in a manner that is dependent upon the rat line, and the functional tone of the serotoninergic projection to the prefrontal cortex is stronger in RHA rats than in RLA rats Barcelona, Spain / Fernández-Teruel, Tobeña, Morón, Torres; Escorihuela et al., 1995a-b; Fernandez-Teruel et al., 1991, also in collaboration with: Oxford, UK/ Flint, Mott; Almería, Spain/ Flores, Moreno; 1992a-b, 1993, 1994, 1997, 1998, 2002a,c; Ferré et al., 1994; Madrid, Spain/ Pellón; Bochum, Germany/ Anselme; Fort Worth, TX, USA/ Papini; Rio-Alamos et al., 2015, 2017b, 2019; Steimer et al., 1998 Bristol, UK/ Lodge; (i)- First evidence that neonatal handling (NH), and/or juvenile-adult environmental enrichment lead to profound lifetime effects on many behavioral/cognitive and endocrine traits of the Roman rats, often eliminating the differences between them. NH significantly improves adult acquisition of two-way active avoidance in RLA rats (ii)- First quantitative genetic study on multiple anxiety-related traits, with > 800 F2 rats Aguilar et al., 2002b, 2003; Escorihuela et al., 1999; Fernandez- of both sexes (hybrids from the inbred RHA and RLA strains), revealing for the first time Teruel et al., 2002b (see also Johannesson et al., 2009) in rats the existence of pleiotropic QTL (“quantitative trait loci”) influencing several conditioned and unconditioned anxiety- and fear-related traits. Supplementary Table 1 (continued) First demonstration of genetic parent-of-origin effects on coping (anxiety-related) behavior in genetically heterogeneous (NIH-HS) and Roman rats Mont et al., 2018 (iii)- Convincing evidence that, besides being anxious and passive coping animals, RLA rats Cuenya et al., 2012, 2015; Gomez et al., 2008, 2009a-c; Manzo display enhanced frustration responses to incentive loss in different paradigms, and might et al., 2014a, 2015; Moron et al., 2010; Papini et al., 2015; Rosas constitute a unique tool for research on the neurobiology of frustration et al., 2007; Sabariego et al., 2011, 2013; Torres and Sabariego 2014; Torres et al., 2005, 2007 (iv)- RHA (but not RLA) rats show a stop codon mutation at cysteine 407 in Grm2 Wood et al., 2017 (see also Fomsgaard et al., 2018; Klein et al., (cys407*; mGlu2 receptor), which allows the RHA strain to represent a naturally-occurring 2014) “knock out” of mGlu2 receptors (v)- As compared to RLA rats, RHA rats exhibit impulsivity in several tasks, impaired Merchan et al., 2019; Moreno et al., 2010; Del Río et al., 2014; attentional/cognitive profiles and alterations of social behavior, decreased volume and/or Río-Álamos et al., 2017a, 2019; Tapias-Espinosa et al., 2019; activity of the medial prefrontal cortex (PFC), hippocampus and amygdala, as well as a number Elfving et al., 2019; Fomsgaard et al., 2018; Klein et al., 2014; of alterations of neurodevelopment-related pre-/postsynaptic markers and in the pyramidal Sánchez-González et al., 2021; Sampedro-Viana et al., 2021 spine density in the PFC, all of which indicate the presence of an immature PFC and a schizophrenia-like phenotypic profile in RHA rats Supplementary Table 1 (continued) LEGEND TO SUPPLEMENTARY TABLE 1.- Relevant endeavors/ findings/achievements from the different groups/laboratories are highlighted in bold italics. Abbreviations.- TWAA: two-way active avoidance. RLA, RHA and RCA: Roman Low-avoidance, Roman High-avoidance and Roman Control-Avoidance (derived from random mating of Wistar rats). RLA/Lu, RHA/Lu, RCA/Lu: these are the corresponding names of the three Roman lines established at Lakehead University (Thunder Bay, Canada) by Dr. P. Satinder (Satinder 1971). MR and MNR: Maudsley Reactive and Maudsley Non-Reactive (MNR/Har/Lu and MR/Har/Lu are the corresponding names of both Maudsley rat lines established at Lakehead University, Ontario, Canada, by Dr. P. Satinder (see Satinder 1971) . TMB and TMD: Tyron Maze Bright and Tyron Maze Dull (see Koene and Vosen 1991). WAG: Wistar Albino Glaxo control strain. Grm2, mGlu2 receptor: metabotropic glutamate 2 receptor. Table S2 Supplementary Table 2 (S2). Effects of anxiolytic or anxiogenic drug treatments on anxiety- related behaviors in RLA and RHA rats Drug Dose Drug class Effect on anxiety References (mg/kg) index/responses ACUTE ANXIOLYTIC-LIKE DRUG TREATMENTS Diazepam 1.0 Anxiolytic BZ Decrease of eating latency Shephard and Broadhurst, more marked in RLA rats 1983 (hyponeophagia anxiety test) l-propranolol 6.0 Anxiolytic β-A-R Decrease of eating latency Shephard and Broadhurst, antagonist more marked in RLA rats 1983 (hyponeophagia anxiety test) Methysergide 6.0 Anxiolytic 5-HT-R Decrease of eating latency Shephard and Broadhurst antagonist more marked in RLA rats 1983 (hyponeophagia anxiety test) Pentobarbital 8.0, Anxiolytic GABAA- Increased avoidance behavior Driscoll and Stübi, 1985 16.0 R chloride channel and decreased freezing agonist response in two-way avoidance acquisition in RLA rats Chlordiazepoxide 2.5 Anxiolytic BZ Increase of entries into the Martin et al., 1982 illuminated open-field-like center of the hexagonal tunnel maze in RLA rats Flumazenil 5.0 Antagonist of BZR Decrease of response failures Fernández-Teruel et al., (with known (i.e. freezing responses) and 1991b anxiolytic-like increase of escape responses in effects at low two-way avoidance acquisition doses) in RLA rats Diazepam 0.3, Anxiolytic BZ Decreased latency to the first Steimer and Driscoll, 2003 1.0 crossing from the dark to the light compartment in the light/dark box anxiety test in RLA rats Diazepam 1.0 Anxiolytic BZ Increased avoidance behavior in Torres et al., 2007 RLA rats in a conflict-like (anxiogenic) one-way active avoidance task (with only 1 s allowed in the safe side) Diazepam 1.0, Anxiolytic BZ Increase in punished drinking in Corda et al., 2018 2.5 the Vogel’s conflict test (similar magnitude in RLA and RHA rats) p-Octopamine (*) 0.25 Trace amine with Increase in two-way active Delacour et al., 1983 (i.c.v.) anxiolytic-like avoidance acquisition of RLA effects In other rats to the level of untreated tests (control) RHA rats Ethanol 0.25 Pro-GABAergic Behavioral disinhibition in the Guitart-Masip et al., 2006a (g/kg) with anxiolytic-like hole-board test in RLA rats: effects in other marked increase of time spent tests head-dipping into the holes containing novel/unknown objects, without changes in locomotor activity. Supplementary Table 2 (continued) PERINATAL OR CHRONIC ANXIOLYTIC-LIKE DRUG TREATMENTS Perinatal flumazenil 3.7 Antagonist of BZ-R Increased avoidance Escorihuela et al., 1995a (given from ED15 to behavior and decrease of PND 14)) freezing responses in two- way avoidance acquisition in RLA rats Perinatal flumazenil 3.5, Antagonist of BZ-R Increased avoidance Ferré et al., 1996 6.3 (given from ED15 to behavior and decrease of PND 14) freezing responses in two- way avoidance acquisition in RLA rats Prenatal diazepam 1.0, Anxiolytic BZ Decrease of freezing Driscoll et al., 1995 3.0 (ED 15 to ED 20) responses and increase of escape responses in the two- way avoidance acquisition task in RLA rats Repeated morphine 14.0, μ-R, d-R, and k-R Increase of avoidance Satinder, 1976b 224.4 agonist (escalating responses in the two-way doses, 5 days) avoidance acquisition task (1 h after last morphine injection) particularly in RLA rats ACUTE ANXIOGENIC DRUG TREATMENTS (OR DRUG WITHDRAWAL-INDUCED ANXIOGENIC-LIKE EFFECT) 5-MeODMT 2.5 Anxiogenic 5-HT-R Increase of eating latency in Shephard and agonist the hyponeophagia test, Broadhurst, 1983 more markedly in RLA rats PTZ 10.0, Anxiogenic GABAA -R Increase of self-grooming Giorgi et al., 2003a 15.0 chloride channel and freezing behavior blocker (anxiety-related responses) in RLA rats. Similar to the effects of tail-pinch stress ZK93426 15.0 Anxiogenic β- Increase of freezing and Giorgi et al., 2003a carboline derivative, tendency to increase self- partial inverse grooming (anxiety-related agonist acting at responses) in RLA rats. BZ-Rs Similar to the effects of tail- pinch stress PTZ 10.0, Anxiogenic GABAA -R More marked decrease of Corda et al., 2018 15.0 chloride channel punished drinking responses blocker in the Vogel’s licking suppression conflict test in RLA than RHA rats Withdrawal from 14.0, μ-R, d-R, and k-R Decrease of avoidance Satinder, 1976b repeated morphine 224.4 agonist (escalating responses in the two-way doses, 5 days) avoidance acquisition task (48 and 96 h after withdrawal) (*) The trace amine p-octopamine has been reported to display anxiolytic-like effects, as it markedly reduced conditioned suppression of locomotor activity in rats (i.e. reverses the suppression of activity of rats exposed to a context associated, through Pavlovian conditioning, with footshocks 24 h before (Delacour and Guenaire, 1983), it improves two-way active avoidance acquisition in Sprague- Dawley rats without affecting, or even reducing, baseline locomotor activity (David et al., 1982). The concentrations of p-octopamine in the brain stem and hypothalamus are negatively associated with the levels of emotional stress (Ennaceur et al., 1986). Abbreviations: BZ, benzodiazepine; BZ-R, benzodiazepine receptor; β-A-R, beta-adrenergic receptor; GABAA-R, g-aminobutyric acid-A receptor; ED, embryonic day; PND, postnatal day; μ-R, d-R, and k-R, μ-, d-, and k- opioid receptors; PTZ, pentylenetetrazole.