REVIEW published: 05 July 2019 doi: 10.3389/fnbeh.2019.00145 A Genetic Model of Impulsivity, Vulnerability to Drug Abuse and Schizophrenia-Relevant Symptoms With Translational Potential: The Roman High- vs. Low-Avoidance Rats Osvaldo Giorgi 1 *, Maria G. Corda 1 and Alberto Fernández-Teruel 2 * 1 Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy, 2 Medical Psychology Unit, Department of Psychiatry and Forensic Medicine, School of Medicine, Institute of Neurosciences, Universitat Autónoma de Barcelona, Barcelona, Spain Edited by: Margarita Moreno, The bidirectional selective breeding of Roman high- (RHA) and low-avoidance (RLA) rats University of Almería, Spain for respectively rapid vs. poor acquisition of active avoidant behavior has generated Reviewed by: two lines/strains that differ markedly in terms of emotional reactivity, with RHA rats Almira Vazdarjanova, Augusta University, United States being less fearful than their RLA counterparts. Many other behavioral traits have been Marta Miquel, segregated along the selection procedure; thus, compared with their RLA counterparts, University of Jaume I, Spain RHA rats behave as proactive copers in the face of aversive conditions, display *Correspondence: a robust sensation/novelty seeking (SNS) profile, and show high impulsivity and an Osvaldo Giorgi giorgi@unica.it innate preference for natural and drug rewards. Impulsivity is a multifaceted behavioral Alberto Fernández-Teruel trait and is generally defined as a tendency to express actions that are poorly albert.fernandez.teruel@uab.cat conceived, premature, highly risky or inappropriate to the situation, that frequently lead Received: 31 January 2019 to unpleasant consequences. High levels of impulsivity are associated with several Accepted: 18 June 2019 neuropsychiatric conditions including attention-deficit hyperactivity disorder, obsessive- Published: 05 July 2019 compulsive disorder, schizophrenia, and drug addiction. Herein, we review the behavioral Citation: Giorgi O, Corda MG and and neurochemical differences between RHA and RLA rats and survey evidence that Fernández-Teruel A (2019) A Genetic RHA rats represent a valid genetic model, with face, construct, and predictive validity, Model of Impulsivity, Vulnerability to to investigate the neural underpinnings of behavioral disinhibition, novelty seeking, Drug Abuse and Schizophrenia-Relevant Symptoms impulsivity, vulnerability to drug addiction as well as deficits in attentional processes, With Translational Potential: cognitive impairments and other schizophrenia-relevant traits. The Roman High- vs. Low-Avoidance Rats. Keywords: Roman high- and low-avoidance rats, genetic animal model, impulsivity, schizophrenia-relevant Front. Behav. Neurosci. 13:145. symptoms, sensation/novelty seeking, vulnerability to drug abuse, mesoaccumbens and mesocortical doi: 10.3389/fnbeh.2019.00145 dopaminergic pathways Frontiers in Behavioral Neuroscience | www.frontiersin.org 1 July 2019 | Volume 13 | Article 145 Giorgi et al. Genetic Animal Model of Impulsivity INTRODUCTION In recent years, it has become apparent that rather than a form of self-medication secondary to typical schizophrenia symptoms Impulsivity is a multifaceted trait that involves premature or medication side effects, substance abuse comorbidity is responses or actions without foresight, often leading to an independent primary disease symptom in schizophrenia adverse or maladaptive consequences. Impaired impulse control (Chambers et al., 2001). Nevertheless, the limited availability and deficits in attention are characteristic, and in some of animal models of substance abuse comorbidity in psychotic cases core aspects, of several neuropsychiatric conditions, disorders based on genetic selection is an important drawback such as attention-deficit hyperactivity disorder, obsessive- in preclinical research on the impact of gene-environment compulsive disorder, antisocial behavior, mania, schizophrenia, interactions on such conditions. Here, we will survey and drug addiction (Dalley et al., 2011; Jupp and Dalley, 2014; experimental evidence supporting the view that the RHA rat Hoptman, 2015; Hayward et al., 2016; Chase et al., 2017; line/strain may be used as a reliable animal model of genetically Dalley and Robbins, 2017). determined vulnerability to substance use comorbidity in Research on the pathophysiological substrate of impulsivity schizophrenia in terms of face, construct, and predictive validity. has benefited from the availability of both, psychometrical and Implications of these findings for investigations on the etiology experimental measures of this multifaceted construct combined and treatment of Impulsive Compulsive Spectrum Disorders are with functional magnetic resonance imaging (fMRI) studies in considered in the present review article. humans, and valid models to assess impulsive behavior either as a trait or a state in animals. An example of animal model of impulsivity is represented by TESTS AND MODELS OF THE the Roman high- (RHA) and low-avoidance (RLA) lines/strains IMPULSIVITY TRAIT AND IMPULSIVE of rats. These rats are bidirectionally selected and bred for ACTIONS/RESPONSES their rapid (RHA) vs. extremely poor (RLA) ability to acquire the two-way active avoidance response in a shuttle box. More Although preclinical and clinical studies have led to relevant than four decades of research have characterized RHA rats advances in our knowledge of some psycho- and neuro-biological as less fearful, anxious and stress-sensitive than their RLA mechanisms underlying impulsivity and its involvement in counterparts (Steimer and Driscoll, 2003; Driscoll et al., 2009; several psychiatric disorders (Jupp and Dalley, 2014; Chase Río-Álamos et al., 2017a,b). Remarkably, compared with RLAs, et al., 2017; Dalley and Robbins, 2017), the currently available RHA rats display an impulsive phenotype, as shown by their treatments for impulsivity and impulsivity-related disorders response profiles in the delayed response latency 20 (DRL- have limited efficacy and application. Thus, rigorously validated 20), schedule-induced polydipsia, and 5-choice serial reaction animal models, which allow manipulation of experimental time (5CSRT) tasks (Zeier et al., 1978; Moreno et al., 2010; conditions that is not possible in humans, are critical to Merchán et al., 2019; see ‘‘The Roman Rats: A Genetic enable progress in our understanding of the psychological, Model of Differential Anxiety, Novelty Seeking, Impulsivity, neurobiological and genetic basis of deficits of impulse control Attention Deficits and Associated Traits’’ section). Moreover, and for the development of innovative therapies (Dalley et al., relative to RLAs, RHA rats display several impairments in 2011; Hayward et al., 2016). schizophrenia-relevant phenotypes, such as prepulse inhibition Of note, the assessment of the validity of animal models (PPI; Oliveras et al., 2015; Río-Álamos et al., 2019), latent ought to address the three dimensions of face, construct, and inhibition (LI; Fernández-Teruel et al., 2006), spatial working predictive validity. Face validity refers to a phenomenological memory (Oliveras et al., 2015) and reversal learning (Río-Álamos similarity between the model and the disorder being modeled. et al., 2019) as well as a trend towards a reduction of some Construct validity implies that the model has a sound theoretical types of social behavior (Coppens et al., 2012; Del Rio et al., rationale and heuristic potential, that is, it can aid in discovering 2014; see ‘‘RHA Rats as a Model of Deficits in Attentional novel characteristics of the modeled condition. The concept of Processes, Cognitive Impairments and Other Features Relevant predictive validity implies that manipulations known to influence for Schizophrenia Research’’ section). These behavioral profiles the pathological state (i.e., clinically effective treatments) should are consistent with findings of a reduced volume and function have similar effects in the model (Willner, 1984). of the medial prefrontal cortex (mPFCx), hippocampus (HC) An important aspect of animal models involves the and amygdala (AMY) of RHA vs. RLA rats (Río-Álamos development of tests, tasks and/or measures that allow the et al., 2017a, 2019). Finally, as it would be expected from a evaluation of behavioral responses reflecting the human model with translational value, compared with RLAs, RHA rats trait that one intends to model. In this regard, for example, also show more intense behavioral sensitization following the the DRL-20, stop signal, delay discounting, schedule- repeated administration of psychostimulants (Corda et al., 2005; induced polydipsia, 5C-SRT, and 5-choice continuous Giorgi et al., 2005a, 2007) and enhanced vulnerability to drug performance (5C-CP) tasks allow measuring impulsivity, abuse/addiction (Fattore et al., 2009), which are associated with impulsive responses and attention in laboratory rodents a more robust mesolimbic dopaminergic tone (Giorgi et al., (Hayward et al., 2016; Dalley and Robbins, 2017). In 1997, 2003, 2005b; Piras et al., 2003; Lecca et al., 2004; see addition, some of these models have the advantage of being ‘‘The Roman Rats as a Genetic Model of Vulnerability to Drug completely translatable to humans (e.g., the stop signal Addiction’’ section). paradigm, delay discounting, 5C-SRT and 5C-CP tests are Frontiers in Behavioral Neuroscience | www.frontiersin.org 2 July 2019 | Volume 13 | Article 145 Giorgi et al. Genetic Animal Model of Impulsivity used in both rodents and humans; Hayward et al., 2016; profiles, display impaired behavioral flexibility (i.e., the ability Dalley and Robbins, 2017). to adapt responses to changing environmental demands) and Another significant aspect concerning animal analogs is the attention, and are often novelty/incentive seekers (Coppens strategy employed to model impulsivity either from an ‘‘etiology- et al., 2010). Numerous studies indicate that the responses focused’’ or a ‘‘behavior to biology’’ perspective. Genetically that characterize the proactive coping style are predominantly engineered rats or mice and brain lesion-based models driven by internal mechanisms or routines (i.e., they are constitute experimental strategies for modeling impulsivity not much sensitive to changes in the environment), whereas from an etiology-focused perspective. Notably, the etiological reactive coping animals are much more dependent on the hypotheses are the main constraints of these models, which environment (Coppens et al., 2010). This difference in the begin by assuming a given pathophysiological mechanism sensitivity to changes in environmental conditions critically and then investigate the resulting phenotype (Jupp et al., influences behavioral flexibility, which is generally higher in 2013; Hayward et al., 2016). Conversely, the ‘‘behavior to subjects characterized by a reactive coping style. For example, biology’’ models use a different strategy, which starts by proactive coping RHA rats -that are also impulsive- are impaired recreating or identifying an impulsive phenotype and then at solving a spatial reversal learning task compared with their follows by investigating its neuropsychological underpinnings. reactive coping RLA counterparts (Escorihuela et al., 1995; Some of these preclinical models select groups of animals Río-Álamos et al., 2019). Thus, proactive coping styles in from a heterogeneous population on the basis of the different experimental animals and in humans are frequently positively characteristics of a behavioral trait or behavioral response associated with impulsivity, behavioral (cognitive) inflexibility related with impulsivity. The Lister-Hooded rats selected for and also with deficits in behavioral inhibition (for a review, see excessive premature (i.e., impulsive) responses in the 5C-SRT Coppens et al., 2010). test (Robinson et al., 2009; Hayward et al., 2016; Dalley and Behavioral inhibition is a trait related to the reactive coping Robbins, 2017) and the Wistar rats stratified for extreme style and anxiety. In this context, anxiety is operationally values of schedule-induced polydipsia (Merchán et al., 2019, defined as the increased susceptibility to signals of punishment, and references therein) are examples of these models of non-reward and novelty, that leads to the expression of reactive impulsive behavior. Other ‘‘behavior to biology’’ models use coping responses, such as freezing or risk assessment in the face selective bidirectional breeding for a given phenotype and of a conflict between incompatible goals/responses (Gray and then systematically evaluate the underlying neurobiological McNaughton, 2000). Conversely, proactive coping individuals mechanisms and associated traits. The latter are especially tend to display disinhibited and impulsive responses/behavior relevant since one would expect from a valid impulsivity under the same conditions (Gray and McNaughton, 2000; Avila model that such associated traits were related to the selected and Torrubia, 2006; Coppens et al., 2010). trait: for example, rats with an impulsive phenotype should Notably, the RHA and RLA rat lines/strains display be more vulnerable to addictive drug taking, compulsive drug differential impulsivity and profound divergences in seeking and relapse. Examples of these models are the low- and associated traits, such as coping style, behavioral inhibition, high-impulsive inbred rats (Belin et al., 2016), and the RHA and behavioral/cognitive flexibility, attention, cognitive ability RLA rats (Escorihuela et al., 1999; Moreno et al., 2010; Tournier (e.g., spatial learning, working memory) and novelty seeking, et al., 2013) that are the main focus of this review article. as described in the following section (Driscoll and Bättig, 1982; Driscoll et al., 1998, 2009). COPING STYLE, BEHAVIORAL FLEXIBILITY, BEHAVIORAL INHIBITION THE ROMAN RATS: A GENETIC MODEL OF AND IMPULSIVITY DIFFERENTIAL ANXIETY, NOVELTY SEEKING, IMPULSIVITY, ATTENTION The concept of coping style arises mainly from the field of DEFICITS AND ASSOCIATED TRAITS research on stress and relates to how an organism deals, or tries to deal, with a threat. In general, it refers to consistent response Behavioral Inhibition and Anxiety profiles in the face of challenges that are similar across various The Roman rat lines were established in Rome in the 1960s situations and stable over time (Coppens et al., 2010). However, through bidirectional selection and outbreeding of Wistar rats coping styles also extend their influence to non-threatening or showing very high (RHA) vs. extremely low (RLA) rates of non-aversive situations, such as appetitive conditions or tasks acquisition of the two-way active avoidance response (Bignami, that involve some kind of conflict between actions that lead 1965, see ‘‘Introduction’’ section). Subsequently, the Swiss to worse consequences (e.g., a fast instrumental response that sublines RHA/Verh and RLA/Verh were derived from the leads to an immediately available small reward) and actions original lines (Driscoll and Bättig, 1982) and other outbred that lead to a better outcome (e.g., a slow, delayed instrumental sublines were established in the USA (Satinder, 1975), France response that leads to a big reward). Two different styles of (Willig et al., 1991; Castanon et al., 1995) and Cagliari, coping behavior, proactive and reactive, are considered in coping Italy (Giorgi et al., 2005b). In addition, two inbred Roman research. Typically, rodents with a proactive coping style show strains, RHA-I and RLA-I, generated through brother/sister impulsive (i.e., premature and poorly conceived) responding mating of the respective Swiss sublines, were established in Frontiers in Behavioral Neuroscience | www.frontiersin.org 3 July 2019 | Volume 13 | Article 145 Giorgi et al. Genetic Animal Model of Impulsivity Barcelona and Germany (Schwegler et al., 1997; Driscoll et al., et al., 2018) and more pronounced fear-potentiated acoustic 1998; Escorihuela et al., 1999). It was soon noticed that the startle (Schwegler et al., 1997; Yilmazer-Hanke et al., 2002; selection for two-way avoidance acquisition did not lead to López-Aumatell et al., 2009a,b). The enhanced behavioral rat lines primarily differing in some general process related inhibition of RLA rats is also observed in instrumental to ‘‘learning ability.’’ In contrast, the Roman lines differ procedures of frustrative reward omission (i.e., extinction) in the emotional responses displayed in stress or anxiety or reward down-shift (Torres et al., 2005; Rosas et al., 2007; paradigms (reviewed by Driscoll and Bättig, 1982; Driscoll Gómez et al., 2009b; Coppens et al., 2012, 2013; Manzo et al., 2009). Accordingly, there is ample experimental evidence et al., 2014b). Finally, another example of the reactive showing that two-way active avoidance learning is blunted by (i.e., behavioral inhibition) vs. proactive coping styles in fear/anxiety (Gray, 1980; Fernández-Teruel et al., 1991b; Gray the Roman lines/strains is that, in the forced swimming and McNaughton, 2000; Vicens-Costa et al., 2011; LeDoux, test, an experimental model that is extensively used for the 2015; LeDoux et al., 2017; Fernández-Teruel and Tobeña, 2018). screening of antidepressant drugs (Porsolt et al., 1977), RLA In fact, RHA rats learn faster and more effectively than their rats display fewer active movements aimed at escaping from RLA counterparts to avoid the electric shock in the two-way the water cylinder (i.e., struggling) and more immobility than active avoidance test, whereas RLA rats perform better than RHA rats (Piras et al., 2010, 2014; Díaz-Morán et al., 2012). RHA rats in some operant and spatial memory tasks (Zeier Moreover, either the subacute or chronic treatment with the et al., 1978; Nil and Bättig, 1981; Driscoll and Bättig, 1982; antidepressants desipramine, chlorimipramine or fluoxetine Willig et al., 1991). significantly decrease immobility in RLA, but not RHA rats In parallel, early studies on emotional aspects showed that (Piras et al., 2010, 2014), supporting the predictive validity of RLA rats were more sensitive to classical Pavlovian aversive the model. conditioning than their RHA counterparts (Imada, 1972) and Notably, it has been reported that GABA-related anxiolytic displayed more robust hormonal responses (i.e., increments drugs decrease behavioral inhibition (or anxiety) of RLA, but not in the plasma concentrations of corticosterone, prolactin, and RHA rats, in some of the above mentioned conflict-based tests ACTH) to several types of acute psychological and physical (Martin et al., 1982; Driscoll and Stübi, 1985; Fernández-Teruel stressors (Gentsch et al., 1981, 1982). These neuroendocrine et al., 1991c; Steimer and Driscoll, 2003; Torres et al., 2007), findings have been replicated in many subsequent studies whereas the anxiogenic drug pentylenetetrazol, a blocker of the (Castanon et al., 1992; Castanon and Mormède, 1994; Steimer chloride channel of the GABA-A receptor, enhances behavioral et al., 1998; Steimer and Driscoll, 2003; Carrasco et al., 2008; inhibition (i.e., anxiety) in the Vogel’s conflict test predominantly Díaz-Morán et al., 2012; Río-Álamos et al., 2017a,b). in the RLA line (Corda et al., 2018). Of relevance in this Anxiety response profiles are markedly different between context is the finding that the function of the GABA-A receptor RHA and RLA rats, as evidenced in experimental procedures (assessed by means of the GABA-stimulated 36 Cl− uptake and involving unconditioned or conditioned conflict. Among GABA-stimulated [3 H]-Zolpidem binding) is reduced in the the former, some of the earliest demonstrations suggesting whole cerebral cortex of RLA vs. RHA rats (Giorgi et al., 1994; between-line differences in anxiety were the increased defecation Bentareha et al., 1998), which may contribute to the divergent and reduced exploratory activity observed in RLA rats in the behavioral inhibition and emotional responses that distinguish open field test (Gentsch et al., 1981, 1982) and their avoidance RHA from RLA rats. of the illuminated center of the hexagonal tunnel maze (Driscoll Gray and McNaughton (2000) and McNaughton and and Bättig, 1982; Martin et al., 1982). These results have been Corr (2004) have proposed that behavioral inhibition, a corroborated in numerous studies (Fernández-Teruel et al., main expression of cognitive anxiety, is a consequence of 1991a, 1992a,b, 1994, 1997, 2002b; Escorihuela et al., 1997, the activation of the ‘‘Behavioral Inhibition System,’’ whose 1999; Steimer and Driscoll, 2003; Estanislau et al., 2013; Tapias- neuroanatomical substrate is the septo-hippocampal system Espinosa et al., 2018) and extended to other novelty-based, (SHS). The activity of the SHS, in close interplay with the unconditioned conflict conditions, such as the hyponeophagia AMY and related circuitry, seems to be responsible for the test, the light/dark box, the elevated plus-maze and the elevated appearance of some species-specific inhibitory responses, such zero-maze, in which RLA rats consistently display higher as freezing or risk-assessment, in the face of situations in which levels of behavioral inhibition and anxiety responses, which there is a conflict between incompatible goals/responses include avoidance of open/illuminated spaces, freezing, reduced or uncertainty (Gray and McNaughton, 2000). That is, exploratory activity and increased self-grooming (Ferré et al., the activation of the SHS, as well as the AMY in more 1995; Steimer et al., 1998; Escorihuela et al., 1999; Fernández- specific situations, leads to responses that characterize Teruel et al., 2002b; Steimer and Driscoll, 2003; Estanislau et al., states of anxiety and/or fear (Gray and McNaughton, 2000; 2013; Río-Alamos et al., 2015; Río-Álamos et al., 2017a,b). LeDoux, 2015; see also Fernández-Teruel and Tobeña, 2018). Moreover, in procedures involving Pavlovian aversive Activation of the central GABAergic system by anxiolytic conditioning or conditioned approach-avoidance conflict, RLA benzodiazepines and other GABA-mimetic drugs decreases rats display, compared to their RHA counterparts, increased the activity of the SHS, and thus reduces behavioral inhibition conditioned freezing (Imada, 1972; López-Aumatell et al., in conflict conditions (Gray and McNaughton, 2000). It is 2009a; Martínez-Membrives et al., 2015), enhanced shock- noteworthy that, compared with their RHA counterparts, induced suppression of drinking (Ferré et al., 1995; Corda RLA rats display a more pronounced neural activation of Frontiers in Behavioral Neuroscience | www.frontiersin.org 4 July 2019 | Volume 13 | Article 145 Giorgi et al. Genetic Animal Model of Impulsivity the HC and AMY, as reflected by increased c-fos expression, and impulsivity are different traits, they show a significant when exposed to different novelty-based conflict situations positive association. This finding has prompted the development (Meyza et al., 2009). Accordingly, the volume of the HC of composite psychometrical measures of ‘‘impulsive sensation and AMY is larger (Río-Álamos et al., 2017a), and the seeking,’’ using psychometrical instruments that combine both neuronal density is higher in both brain areas of RLA traits into a single construct (Zuckerman, 1996; Roberti, 2004; vs. RHA rats (Garcia-Falgueras et al., 2012; Gómez et al., Magid et al., 2007). 2009c). In addition, the activity of the phospholipase C The RHA rats encompass many characteristics that are signaling cascade is higher in the HC of RLA vs. RHA rats consistent with a model of ‘‘impulsive sensation seeking.’’ Part (Sallés et al., 2001). of the evidence reviewed above, such as the deficit of RHA rats Collectively, the experimental findings reviewed above in the DRL20 paradigm, in which they are less able to inhibit support the view that RHA rats are less anxious and irrelevant responses than their RLA counterparts (Zeier et al., more behaviorally disinhibited than RLA rats and other 1978), or the behavior of RHA vs. RLA rats in some learning rat strains/stocks used as external controls, such as Wistar tasks in several types of mazes (Nil and Bättig, 1981; Driscoll rats or the ‘‘National Institutes of Health Heterogeneous Rat and Bättig, 1982; Willig et al., 1991), had already suggested Stock’’ (NIH-HS) rats (Gómez et al., 2009a; López-Aumatell that deficits of impulse control in RHA rats could play a role et al., 2009b; Díaz-Morán et al., 2012; Estanislau et al., 2013; in their deficient performance in those tasks. Accordingly, it Martínez-Membrives et al., 2015). has been reported that inhibitory control is impaired in RHAs compared with RLA rats, as shown by an increased number of Sensation Seeking and Impulsivity premature responses made by the former in the 5-CSRT task As mentioned in ‘‘Coping Style, Behavioral Flexibility, Behavioral (Moreno et al., 2010). In a delay discounting task, RHA rats Inhibition and Impulsivity’’ section, the proactive coping style also display enhanced impulsive choice and prefer the immediate of RHA rats is associated with behavioral disinhibition and and smaller reward as opposed to a delayed larger reinforcement novelty/sensation seeking. In this regard, the relative behavioral (Moreno et al., 2010). In addition, in the procedure of disinhibition of RHA vs. RLA rats is also apparent in tests schedule-induced polydipsia, the RHA strain shows stronger measuring the preference for novelty which involves some acquisition of the adjunctive responses, and a higher asymptotic degree of ‘‘approach-avoidance’’ conflict and are considered to response level of both water intake and licking responses than capture more specifically the sensation/novelty seeking (SNS) RLA rats (Moreno et al., 2010; see also Klein et al., 2014; trait. Such tests include the novel object exploration test, the Merchán et al., 2019). ‘‘Y’’ maze, familiar vs. unfamiliar spaces, which include novel Consistent with the contention that they represent an objects and novel/unknown spatial distributions (Pisula, 2003), impulsive phenotype, RHA rats display a higher frequency and the hole-board test with unfamiliar objects under the of lever pressing than their RLA counterparts during the holes (File and Wardill, 1975). In these tests, compared with acquisition phase in an unpredictable operant conditioning the RLA strain and, in some measures/tests, also with the paradigm and during the extinction phase upon appetitive outbred NIH-HS strain, RHA rats consistently display more instrumental conditioning (Gómez et al., 2009a; Moreno et al., intense exploration of the novel/unfamiliar objects or spaces 2010; Coppens et al., 2012, 2013; Klein et al., 2014). Moreover, (Fernández-Teruel et al., 1992b, 1997; Escorihuela et al., 1999; RHA rats are more perseverant than RLAs at pressing the Pisula, 2003; Estanislau et al., 2013; Manzo et al., 2014a; active lever during the extinction phase of an intravenous Cuenya et al., 2016). cocaine self-administration program (Fattore et al., 2009; see The SNS trait in humans, cats and rats is characterized by high ‘‘The Roman Rats as a Genetic Model of Vulnerability to levels of exploratory and risk-taking behaviors and is commonly Drug Addiction’’ section). Thus, the RHA phenotype includes associated with impulsiveness and a tendency to experiment characteristics of both the SNS and impulsivity traits. with drugs of abuse (Bardo et al., 1996; Siegel, 1997). SNS cats, The absence of strain-dependent differences in home cage for example, show increased exploratory behavior and lowered activity (Meyza et al., 2009; Estanislau et al., 2013) as well as efficiency in bar pressing responses during an inhibitory DRL the finding that both Roman lines display similar lever press task (i.e., an appetitive instrumental conditioning paradigm in responding during the acquisition of an appetitive operant task which reward is obtained only following low response rates; under a fixed ratio-1 (Coppens et al., 2013), argues against the Saxton et al., 1987a,b). Importantly, a similar behavior has been possibility that the distinct impulsive responding of the two reported in RHA rats (Zeier et al., 1978). lines/strains is due to differences in motor activity. Regarding the neurophysiological basis of SNS, an interesting Notably, although RHA rats show a more impulsive early finding is that, like SNS humans and cats, RHA rats are behavioral profile than their RLA counterparts, it is clear visual evoked potential augmenters at the brain cortical level, that they are capable of displaying response inhibition under whereas RLA rats (as well as the Wistar rats used for comparison) threatening conditions; thus, RHA rats show high levels are visual evoked potential reducers (Siegel and Driscoll, 1996; of conditioned freezing behavior, either when exposed to Siegel et al., 1996; Siegel, 1997). a cue (López-Aumatell et al., 2009a) or a conditioned Studies in humans have shown that behavioral disinhibition is context during Pavlovian or operant aversive conditioning a component of sensation seeking and that this trait is moderately (López-Aumatell et al., 2009a,b; Díaz-Morán et al., 2012; correlated with impulsivity. Thus, although sensation seeking Martínez-Membrives et al., 2015). Frontiers in Behavioral Neuroscience | www.frontiersin.org 5 July 2019 | Volume 13 | Article 145 Giorgi et al. Genetic Animal Model of Impulsivity A large body of experimental evidence has established that RHA RATS AS A MODEL OF DEFICITS IN the mesolimbic dopamine (DA) system is a key component of the neural circuitry mediating brain reward (Wise, 2002). ATTENTIONAL PROCESSES, COGNITIVE This system consists of DA neurons in the ventral tegmental IMPAIRMENTS AND OTHER FEATURES area (VTA) of the mesencephalon that project to forebrain RELEVANT FOR SCHIZOPHRENIA regions such as the nucleus accumbens (Acb), mPFCx, RESEARCH AMY, and HC. Activation of the mesolimbic DA system plays a pivotal role in sensation seeking behavior (Bardo As mentioned previously, a proactive coping style is often et al., 1996) and in the reinforcing effects of drugs of associated with impairments in attention and cognitive abuse (Wise, 2002; Pierce and Kumaresan, 2006; see ‘‘The flexibility, as well as heightened impulsivity (for a review Roman Rats as a Genetic Model of Vulnerability to Drug see Coppens et al., 2010). These traits have in turn been Addiction’’ section). associated with schizophrenia in patients (Brown et al., 2018; Ho It has been shown that the density of D2 DA auto-receptors et al., 2018). Thus, using both psychometric impulsivity scales (D2-autoR) is lower in the substantia nigra/VTA of RHA and the delay discounting task (a measure of action planning and vs. RLA rats (Tournier et al., 2013), consistent with reports impulse control in which higher rates of reward discounting, due relating SNS with low midbrain DA D2-autoR density in to the preference of smaller and immediate rewards over delayed humans (Zald et al., 2008). Moreover, the density of postsynaptic and larger ones, reflect enhanced impulsivity), it has been DA D2/D3 receptors is lower in the striatum and nucleus shown that impulsivity measures are positively associated in a accumbens (Acb) of RHA vs. RLA rats and it has been consistent manner with schizophrenia, schizoaffective disorder, shown that striatal DA D2 receptor availability is inversely and schizophrenia risk in unaffected biological relatives of correlated with novelty seeking behavior of Roman rats in the patients (Ahn et al., 2011; Brown et al., 2018; Ho et al., 2018). In hole-board test (Tournier et al., 2013). Importantly, sensation addition, the presence of heightened impulsivity in schizophrenia seeking in humans has also been negatively associated with is paralleled by impairments in working memory (Ahn et al., striatal D2 receptor availability (Gjedde et al., 2010). Taken 2011; Brown et al., 2018). together, the above mentioned findings and the effects of Therefore, we considered of interest to investigate whether dopamine-mimetic psychostimulants on striatal D2 receptor RHA rats would also display cognitive and attentional availability and on the extracellular concentrations of DA in impairments and other schizophrenia-relevant phenotypes. the terminal fields of the mesolimbic dopaminergic projections In this context, more than two decades ago it was demonstrated support the view that the functional tone of the mesolimbic that there were marked differences in spatial cognitive abilities dopaminergic system is more intense in impulsive sensation between the Roman rat lines. Thus, spatial reference learning seekers such as RHAs than RLA rats (Giorgi et al., 2007; (i.e., place learning) in the Morris water maze was impaired Tournier et al., 2013). in RHA rats (Driscoll et al., 1995; Escorihuela et al., 1995). In studies using rats selected for impulsivity, i.e., behaviorally Moreover, RHA rats also were impaired in a reversal place task, separated in extreme ‘‘high impulsive’’ (HI) vs. ‘‘low impulsive’’ suggesting a blunted behavioral/cognitive flexibility relative to (LI) groups according to their levels of premature responding in their RLA counterparts (Escorihuela et al., 1995; Fernández- the 5-CSRT task, it was found that HI animals had decreased Teruel et al., 1997). These early findings have been replicated D2/D3 receptor availability in the Acb, and D2/D3 receptors and extended by showing that RHAs also exhibit spatial working negatively predicted impulsive behavior (Dalley et al., 2007; memory deficits, as compared with both RLA rats and the see also Barlow et al., 2018). This is consistent with the genetically heterogeneous NIH-HS rats (Willig et al., 1991; aforementioned findings in the Roman rats and with a similar Aguilar et al., 2002; Oliveras et al., 2015, 2016). D2/D3 receptor profile found in ADHD patients (Buckholtz It is noteworthy in this context that the impairments in et al., 2010; Ghahremani et al., 2012). working memory of schizophrenic patients may be due, at Finally, a recent fMRI study in a large sample of healthy least in part, to alterations in cortical GABAergic inhibitory and distressed humans has shown that the activity of the left transmission. Accordingly, it has been shown that, in individuals ventrolateral prefrontal cortex and bilateral ventral striatum, with schizophrenia, a deficiency in brain derived neurotrophic including the Acb, during an ‘‘uncertain reward expectancy’’ factor- (BDNF-) mediated signaling combined with decreased paradigm is positively related with impulsive sensation seeking levels of the GABA synthetizing enzyme, GAD67, results (Chase et al., 2017). This is also in line with the proposal of in reduced inhibitory neurotransmission of GABA neurons an enhanced functional tone of the mesolimbic dopaminergic (i.e., basket cells) in the dorsolateral prefrontal cortex pathway in impulsive sensation seekers like RHA rats (Giorgi (Lewis et al., 2005; Kimoto et al., 2014). This deficiency in et al., 2007). GABA-mediated transmission leads to a decreased inhibition of To sum up, RHA rats show considerable similarities pyramidal neurons that have been hypothesized to contribute with impulsive and sensation seeking humans regarding SNS, to altered gamma oscillations and impaired working memory in impulsivity, visual evoked potentials, and the underlying schizophrenia (Lewis et al., 2005). In view of the above findings it mesolimbic DA transmission-related parameters. These findings would be worthwhile to evaluate GABAergic transmission in the highlight the face and construct validity of RHA rats as a genetic mPFCx (corresponding to the dorsolateral frontal cortex of the model of impulsivity and SNS. human brain) of RHA and RLA rats, since our previous results Frontiers in Behavioral Neuroscience | www.frontiersin.org 6 July 2019 | Volume 13 | Article 145 Giorgi et al. Genetic Animal Model of Impulsivity concerning GABA-stimulated 35 Cl− uptake were performed in in this neurodevelopmental model of schizophrenia are closely the whole cerebral cortex (Giorgi et al., 1994; Bentareha et al., reminiscent of those observed in psychostimulant-sensitized 1998; see ‘‘The Roman Rats: A Genetic Model of Differential RHA rats (Giorgi et al., 2005b, 2007; see also ‘‘The Roman Rats Anxiety, Novelty Seeking, Impulsivity, Attention Deficits and as a Genetic Model of Vulnerability to Drug Addiction’’ section). Associated Traits’’ section). Notably, an interesting recent development is the finding that, LI and PPI of the startle response are attention-related compared with their RLA counterparts, RHA rats display a severe processes that are impaired in schizophrenia and other diseases, disruption of the dimeric metabotropic glutamate-2 (mGlu2)/5- such as bipolar disorder (Gray et al., 1991; Swerdlow et al., HT2A receptor complex consisting in a dramatic reduction of the 1994, 1996; Cromwell et al., 2008; Lubow and Weiner, 2010; cortical, hippocampal and striatal density of mGlu2 receptors, Kohl et al., 2013). The procedures used to evaluate LI and PPI associated with an increase of 5-HT2A receptor density in the are similar in rodents and humans, and the performances in frontal cortex (Klein et al., 2014; Fomsgaard et al., 2018). This both paradigms are currently considered as endophenotypes of molecular profile is reminiscent of what has been found in schizophrenia (Gray et al., 1991; Powell and Miyakawa, 2006; the cortex of drug-free schizophrenic patients (González-Maeso Lubow and Weiner, 2010; Jones et al., 2011; Swerdlow and Light, et al., 2008). Accordingly, it has been shown that the dimeric 2016). Notably, RHA rats display deficient LI of the two-way mGlu2/5-HT2A receptor complex is critically involved in the active avoidance response compared with Sprague-Dawley rats pharmacologic effects of atypical antipsychotics; thus, clozapine (Fernández-Teruel et al., 2006). Likewise, compared with RLAs, does not decrease locomotion in rodents with a disruption RHA rats show impaired LI of the fear-potentiated startle (Esnal of the dimeric mGlu2/5-HT2A receptor complex (González- et al., 2016). Maeso et al., 2008; Kurita et al., 2012). Therefore, the alterations In line with these strain-related differences in LI, we have observed in this complex in RHA rats may at least partly shown in a series of studies that RHA rats display clear account for some of the phenotypical schizophrenia-related traits and consistent deficits of PPI of the acoustic startle response observed in this strain and the almost complete lack of enhancing compared with RLAs (Del Rio et al., 2014; Oliveras et al., effect of clozapine on either the baseline or MK-801-impaired 2015, 2016, 2017; Río-Alamos et al., 2015; Río-Álamos et al., PPI performance (Oliveras et al., 2017). 2017a,b, 2019; Tapias-Espinosa et al., 2018, 2019) and that PPI On the other hand, serotonin transmission has also been deficits predict spatial working memory impairments (Oliveras related also to impulsivity (Dalley and Robbins, 2017). Thus, et al., 2015). Altogether, the above mentioned cognitive and in RHA rats, but not RLAs, there is a positive correlation attentional profiles of RHA vs. RLA rats suggest that the former (r = 0.94, p = 0.02) between 5-HT2A receptor density and may represent a model of schizophrenia-relevant features. This premature responses in the 5-CSRT task (Klein et al., 2014). This is further supported by the increased mesolimbic/mesostriatal is consistent with findings from studies in rodents and humans dopaminergic functional tone of RHA rats (Giorgi et al., 2007; in which the pharmacological blockade of the 5-HT2A receptor Tournier et al., 2013), their enhanced sensitivity to the locomotor produces reductions of several types of impulsive responses and DA releasing effects of acute and chronic psychostimulants (Klein et al., 2014; Dalley and Robbins, 2017). These findings (Corda et al., 2005; Giorgi et al., 2005a,b, 2007; Guitart-Masip suggest that 5-HT2A receptors are involved in impulsivity and, et al., 2008), and by the finding that, relative to RLA rats, RHAs more specifically, that they may facilitate at least some forms of exhibit some impairments in social behavior (Coppens et al., impulsive behavior (reviewed by Klein et al., 2014; see also Dalley 2012; Del Rio et al., 2014). and Robbins, 2017). It is noteworthy that PPI of the acoustic startle is further Altogether, the above reviewed behavioral, pharmacological, impaired by the non-selective DA D1/D2 receptor agonist molecular and neuroanatomical profiles point to RHA rats apomorphine and improved by the DA D2/D3 receptor as a model exhibiting several phenotypical characteristics antagonist haloperidol in RHAs but not RLA rats relevant for impulsivity, sensation seeking, and schizophrenia (Oliveras et al., 2017). research. These phenotypes include attentional and cognitive Two additional lines of evidence support the view that RHA impairments, deficits in social behavior, premature responding rats may be considered as a putative model of schizophrenia- and waiting impulsivity, enhanced mesolimbic dopaminergic relevant symptoms/features. Firstly, social isolation rearing activity and schizophrenia-like alterations of cortical mGlu2 and induces deleterious effects on PPI, anxiety, and spatial reference 5-HT2A receptors. memory only in RHA rats (Oliveras et al., 2016). Second, Finally, it has recently been shown that, compared with their in Sprague-Dawley rats, bilateral neonatal lesions of the RLA counterparts, RHA rats exhibit significant reductions of the ventral hippocampus (NVHLs), a neurodevelopmental model volumes of the mPFCx and HC [measured by means of magnetic of schizophrenia, result in enhanced locomotor activation and resonance imaging (MRI)] as well as dramatically enlarged stereotypies in adult rats upon the acute administration of lateral ventricles (Río-Álamos et al., 2017a, 2019). In addition, amphetamine (Lipska and Weinberger, 2000). Moreover, in PPI-elicited neural activity of the prefrontal cortex (as measured adult NVHL rats, a challenge with amphetamine elicits an by c-fos activation) is lower in RHA than RLA rats (Tapias- augmented increase in DA output in the core (AcbCo) and, Espinosa et al., 2019). These neuroanatomical and functional at the same time, an attenuated dopaminergic response in the alterations are reminiscent of those observed in schizophrenic shell (AcbSh) of the Acb, as compared with shams (Corda et al., patients and provide further support to the contention that RHA 2006). Importantly, the effects of the amphetamine challenge rats may constitute a genetic model of schizophrenia-relevant Frontiers in Behavioral Neuroscience | www.frontiersin.org 7 July 2019 | Volume 13 | Article 145 Giorgi et al. Genetic Animal Model of Impulsivity features with face, construct, and predictive validity (reviewed by The line-related differences in the effects of acute morphine Río-Álamos et al., 2019). and psychostimulants on the mesolimbic dopaminergic transmission suggested that the Roman lines also may differ in the responsiveness of their neural circuits of reward to other THE ROMAN RATS AS A GENETIC MODEL appetitive stimuli. Accordingly, compared with RLA rats, RHAs OF VULNERABILITY TO DRUG ADDICTION have been shown to display higher preference for ethanol and larger increases in DA output in the AcbSh after acute ethanol A combination of environmental and genetic factors underlies intake (Fernández-Teruel et al., 2002a; Manzo et al., 2012, 2014a; the vulnerability to develop a drug addiction (Nestler, 2001, Corda et al., 2014). Furthermore, RHA rats also display higher 2000; Kreek et al., 2005a). Accordingly, interacting with the preference for saccharin solutions (Razafimanalina et al., 1996; direct effects of abused drugs, environmental and genetic factors Fernández-Teruel et al., 2002a) and palatable food (Giorgi et al., may induce the transition from casual, intermittent drug use in preparation) and show more intense sexual motivation than to regular intake, the progression from abuse to compulsive their RLA counterparts (Sanna et al., 2017, 2019). Of note, drug seeking and taking (i.e., addiction), and the propensity for palatable food intake and sexual activity are associated with a repeated relapse even after a long-term drug-free state (Kreek larger increment in accumbal DA output in RHA than RLA rats et al., 2005a,b; Everitt and Robbins, 2016). (Giorgi et al., in preparation; Sanna et al., 2017, 2019). In this section, we examine experimental evidence supporting The above findings prompted us to study whether the the view that the Roman lines represent a valid model to Roman lines also differ in the propensity to develop behavioral investigate how and to what extent the genetic background sensitization upon repeated administration of drugs of abuse. influences the neural and behavioral traits involved in the major Behavioral sensitization is characterized by a progressive increase features of the individual vulnerability to addiction, including in the intensity of locomotor activation and stereotypes high sensitivity to the acute effects of drugs of abuse, the upon repeated exposure to a constant dose of a drug, development of sensitization upon repeated administration, and such as psychostimulants and opiates, or by a greater the propensity to self-administer addictive drugs. response on re-challenge with a lower dose of drug than Early work in the 1980s–90s provided evidence suggesting used in the initial chronic-intermittent exposure (Segal and that the behavioral patterns distinguishing the Roman rat lines Kuczenski, 1987; Pierce and Kalivas, 1997; Vanderschuren may be mediated, at least in part, by differences in the functional and Kalivas, 2000). This increased response is believed to properties of the mesolimbic and mesocortical dopaminergic reflect long lasting adaptations in neural circuits involved in projections. Thus, it was shown that: (i) various stressors motivation and reward (Nestler, 2001; Robinson and Berridge, activated the mesocortical dopaminergic pathway in RHAs but 2001; Everitt and Wolf, 2002; Li et al., 2004). Accordingly, not RLA rats (D’Angio et al., 1988; Giorgi et al., 2003); (ii) repeated exposure to psychostimulants enhances the incentive RHA rats showed a faster turnover rate of DA in the caudate motivational properties of addictive drugs, facilitates drug nucleus (Driscoll et al., 1990) and displayed more intense self-administration (Horger et al., 1990; Piazza et al., 1990; stereotypies and yawning than RLA rats upon acute challenge Mendrek et al., 1998; Lorrain et al., 2000), and potentiates the with apomorphine (Driscoll et al., 1985; Gimenez-Llort et al., responses to conditioned rewards (Shippenberg and Heidbreder, 2005; Sanna et al., 2013); and (iii) the density of DA D1 receptors 1995; Taylor and Horger, 1999; for a review, see Giorgi et al., in the Acb was higher in RHA vs. RLA rats (Giorgi et al., 1994; 2007). The locomotor effects observed following the repeated Guitart-Masip et al., 2006). administration of psychostimulants or morphine consistently The mesolimbic dopaminergic pathway has long been indicate that the Roman rat lines differ markedly in the considered to play a major role in mediating the reinforcing susceptibility to develop behavioral sensitization (Piras et al., effects of psychostimulants, opiates, nicotine, ethanol, and 2003; Corda et al., 2005; Giorgi et al., 2005a,b, 2007): RHA cannabinoids (Pierce and Kumaresan, 2006). Thus, the above- rats displayed a significant increment in locomotor activity mentioned differences between the Roman lines, together after a challenge dose of each drug given several days/weeks with differences in sensation seeking and impulsive behavior, upon completion of the repeated drug treatment whereas no prompted us to investigate how drugs of abuse affect behavior enhanced locomotor activity in response to the challenge drug and central DA function in both rat lines and whether dose was observed in RLA rats (Piras et al., 2003; Corda et al., there are differences in addiction liability between them. In 2005; Giorgi et al., 2005a, 2007; Guitart-Masip et al., 2008; this context, and in line with the hypothesis that RHA rats Tournier et al., 2013). would be more responsive to drugs of abuse than their RLA Moreover, brain microdialysis assays revealed that the counterparts, we found that acutely administered morphine challenge with cocaine, amphetamine or morphine elicited larger and the psychostimulants cocaine or amphetamine elicit larger increases in DA output in the AcbCo of RHA than RLA increments in DA output, as measured by brain microdialysis, in rats that had respectively received repeated doses of cocaine, the AcbSh than the AcbCo of RHA rats, whereas such difference amphetamine or morphine (Piras et al., 2003; Giorgi et al., 2005b, is not present in RLA rats (Lecca et al., 2004). Moreover, the three 2007). In parallel, and only in RHA rats, the drug challenges drugs induce a higher increase of locomotor activity in the former induced an attenuated dopaminergic response in the AcbSh. It line (Giorgi et al., 1997, 2005a,b; Piras et al., 2003; Lecca et al., is remarkable that the above mentioned repeated drug treatment 2004; reviewed by Giorgi et al., 2007). schedules, which induced behavioral sensitization only in RHA Frontiers in Behavioral Neuroscience | www.frontiersin.org 8 July 2019 | Volume 13 | Article 145 Giorgi et al. Genetic Animal Model of Impulsivity rats, produced concomitant neural adaptations in the AcbCo and Taylor, 1999). Accordingly, in RHA rats behaviorally sensitized AcbSh exclusively in this rat line (Giorgi et al., 2007). following chronic treatment with cocaine, but not in their RLA Behavioral and neurochemical sensitization to abused drugs counterparts, the dopaminergic transmission in the mPFCx is is thought to play a key role in several addiction-related markedly reduced (Giorgi et al., in preparation). Furthermore, features, such as compulsive drug-seeking and the long-lasting compared with their RLA counterparts, RHA rats show a smaller vulnerability to relapse (see Fattore et al., 2009 and references frontocortical volume (Roberti, 2004; Río-Álamos et al., 2019) therein). Therefore, we considered of interest to investigate and a reduced activation of the mPFCx upon exposure to PPI the susceptibility of RHA and RLA rats to develop drug testing and a variety of novelty-related situations (Meyza et al., self-administration. To this aim, we assessed the acquisition, 2009; Río-Álamos et al., 2019; Tapias-Espinosa et al., 2019). maintenance, extinction, reinstatement and reacquisition of Substance use comorbidity is a frequent event in many intravenous self-administration of cocaine in RHA and RLA psychiatric disorders and is particularly prevalent in rats in an operant FR-1 task (Fattore et al., 2009). It was found schizophrenic populations (Selzer and Lieberman, 1993). that RHA rats displayed substantially more frequent lever-press Thus, dual diagnosis in schizophrenia is associated with a operant responding than their RLA counterparts during all the remarkably high prevalence of cocaine, amphetamine, alcohol, phases of cocaine self-administration. cannabis, and nicotine use (DeQuardo et al., 1994; Buckley, The persistently higher frequency of active lever responding 1998; Dalack et al., 1998; Dixon, 1999). of RHA vs. RLA rats during the maintenance phase of cocaine A widely held neurobiological explanation for substance use self-administration could not be attributed to a generalized comorbidity in schizophrenia is the self-medication hypothesis, rate effect in RHA rats since the inactive lever responding which postulates that patients use addictive drugs to relieve was not increased relative to RLA rats. Furthermore, extinction aversive disease symptoms or the adverse side effects of tests were conducted in the absence of cocaine reinforcement, medication. Hence, this hypothesis posits that susceptibility to and yet cocaine-seeking responses at the active lever in drug abuse is a reaction to the psychotic disorder or medication RHA rats were more frequent relative to RLAs and required side effects, and thus represents a secondary symptom (Buckley, almost twice as many test sessions to reach extinction criteria 1998; Dalack et al., 1998; Krystal et al., 1999). In contrast, (Fattore et al., 2009). experimental evidence accumulated in the last years supports After 3 weeks of withdrawal, when RHA and RLA rats had the view that the pathologic substrate of schizophrenia may extinguished to similar low response levels, non-contingently contribute to the susceptibility to addiction by facilitating administered cocaine injections induced significantly more the functional activity of the neural circuitry that mediates frequent responses at the active lever in RHAs relative positive reinforcement (Chambers et al., 2001). Two key to RLA rats, whereas saline injections were without effect lines of evidence support this primary addiction hypothesis: in both lines. Collectively, these results suggest that RHA (i) the putative neuropathology underlying schizophrenia rats are more susceptible than RLAs to relapse to cocaine involves alterations in neural circuits that regulate positive seeking, whether induced by exposure to the cocaine-associated reinforcement, incentive motivation, novelty seeking, context (i.e., extinction), or to a priming injection of cocaine behavioral inhibition, and addictive behavior as well as (i.e., reinstatement). In addition, these findings support the schizophrenia-relevant attentional/cognitive impairments contention that, in RHA rats, behavioral sensitization may (Chambers et al., 2001 and references therein); and (ii) be involved in relapse-related processes (Fattore et al., 2009). experimental manipulations that model neuropathologic Importantly, the AcbCo has been implicated in the reinstatement and behavioral aspects of schizophrenia in animals (e.g., the of cocaine-seeking induced by the administration of a priming NVHL model, Lipska and Weinberger, 2000) also facilitate dose of the drug or by exposure to drug-related cues (Ito positive reinforcement and the incentive motivational et al., 2004; Hollander and Carelli, 2007). This experimental effects of rewarding stimuli (Chambers and Self, 2002). evidence is consistent with the view that the AcbCo and its An implicit feature of this hypothesis is that both the afferent glutamatergic projections originating in the mPFCx schizophrenia syndrome and vulnerability to addiction are play a key role in cocaine-induced relapse (McFarland et al., primary disease symptoms, each directly caused by common 2003). Accordingly, as mentioned above, the functional tone neuropathologic substrates. of the dopaminergic transmission is markedly increased in Most important, the results reviewed herein show that RHA the AcbCo of RHA rats behaviorally sensitized to cocaine rats include behavioral and neurochemical traits related with (Giorgi et al., 2007). both, schizophrenia and addiction. Therefore, RHA rats may Besides the central role of the mesolimbic dopaminergic represent a promising model of substance use comorbidity with projection to the Acb, other brain areas and neural circuits face, construct, and predictive validity. may be involved in the susceptibility of RHA rats to develop cocaine seeking and taking upon chronic exposure to the same drug. For instance, a dysfunction of the frontocortical projections AN INTEGRATED PERSPECTIVE to limbic nuclei, which is thought to be a consequence of long-term exposure to drugs of abuse, may lead to a deficient Collectively, the findings reviewed herein provide a detailed inhibition of inappropriate/irrelevant responses during operant account of the major traits that distinguish RHA from RLA extinction or in the presence of drug-paired stimuli (Jentsch and rats, from coping style, impulsivity, and behavioral inhibition Frontiers in Behavioral Neuroscience | www.frontiersin.org 9 July 2019 | Volume 13 | Article 145 Giorgi et al. Genetic Animal Model of Impulsivity FIGURE 1 | Simplified model of the functions of the mesocorticolimbic dopaminergic circuit and its modulation by limbic and cortical areas in relation to their differential involvement in behavioral inhibition/disinhibition, impulsivity, schizophrenia-like features, and drug seeking/addiction in Roman high- (RHA) and low-avoidance (RLA) rats. In this schematic diagram, the arrow thickness and character size represent the intensity of the functional tone or the receptor density of the corresponding brain area or neural circuit, respectively. The lower neuronal activity and volume of the medial PFC (mPFC), the HC, and the AMY, as well as the increased density of 5-HT2AR and the markedly decreased density of mGlu2R 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. Collectivelly, the lowered function of the mPFC, the HC, and the AMY, along with the increased functional tone of the mesolimbic dopaminergic system of RHA rats favor behavioral disinhibition, impulsive actions/responses, attentional/cognitive deficits and vulnerability to drug addiction. Modified from Probst and van Eimeren (2013). Abbreviations: mPFC, medial prefrontal cortex; HC, hippocampus; AMY, amygdala; Acb, nucleus accumbens; VTA, ventral tegmental area; mGlu2R, metabotropic glutamate type 2 receptors; 5-HT2AR, serotonin type 2A receptors; D2R, dopamine type 2 receptors; D1R, dopamine type 1 receptors. Frontiers in Behavioral Neuroscience | www.frontiersin.org 10 July 2019 | Volume 13 | Article 145 Giorgi et al. Genetic Animal Model of Impulsivity through attention and cognitive ability to novelty seeking, with RLA and heterogeneous/outbred rats, RHAs appear to be drug seeking, mesocorticolimbic dopaminergic transmission, unique in that they include all the phenotypes mentioned above, and schizophrenia-relevant behaviors. and this makes this rat strain a promising heuristic tool to A hypothetical integrative model of the relationships among investigate relationships among these traits and their underlying the main traits of the particular neurobehavioral profiles of neurobiological/genetic bases. the Roman rats is shown in Figure 1. We acknowledge that Finally, according to the primary addiction hypothesis, the proposed model is a simplification and does not take into the pathophysiologic underpinnings of schizophrenia facilitate account the role of other neurotransmitters that may be involved the vulnerability to substance use disorder by potentiating in the neurobehavioral traits that distinguish the Roman lines. the functional activity of the neural circuitry that mediates It is hypothesized that the lower activity and volume of the positive reinforcement thereby leading to the high prevalence of mPFC, the HC, and the AMY, together with the higher density substance use comorbidity in schizophrenics. Hence, the distinct of 5-HT2A receptors and the dramatically decreased density of neurobehavioral profile of RHA rats makes this strain a valid mGlu2 receptors in the frontal cortex of RHA vs. RLA rats may model of dual diagnosis schizophrenia. determine a hyper-functional glutamatergic cortical system in RHA rats (Meyza et al., 2009; Klein et al., 2014; Río-Álamos et al., AUTHOR CONTRIBUTIONS 2017a, 2019; Wood et al., 2017; Tapias-Espinosa et al., 2019). This in turn would elicit an increment in the functional tone All authors contributed to the bibliographic research, of the dopaminergic VTA neurons projecting to the Acb (Elert, were involved in writing the manuscript, and approved its 2014) and a decrease in the functional tone of the mesocortical final version. dopaminergic system of RHA rats (Dalley et al., 2007; Giorgi et al., 2007; Probst and van Eimeren, 2013; Tournier et al., FUNDING 2013; Elert, 2014; Klein et al., 2014; Dalley and Robbins, 2017; Fomsgaard et al., 2018). In addition, the decreased density of The authors and part of the work reviewed herein are supported, DA D2 receptors together with the increased density in DA or have received support from grants ARS (Autonomous Region D1 receptors in the limbic system of RHAs relative to RLA rats of Sardinia, L.R. 7/2007, Project Code No. CRP-59842) to OG (Giorgi et al., 1994, 2007; Guitart-Masip et al., 2006) may also and PSI2017-82257-P to AF-T, OG and MC. AF-T is the recipient contribute to the more robust functional tone of the mesolimbic of the ‘‘ICREA-Academia 2013’’ prize. dopaminergic system of the former line. It is proposed that this integrated neural circuitry underlies novelty seeking (Tournier ACKNOWLEDGMENTS et al., 2013), impaired impulse control (Dalley et al., 2007), vulnerability to drug sensitization and abuse (Giorgi et al., 2007; The authors wish to thank Dr Peter Driscoll and all the Fattore et al., 2009; Tournier et al., 2013) and schizophrenia- co-workers quoted in the list of references for their invaluable relevant attentional/cognitive impairments (Wakabayashi et al., and continuing help throughout the long Roman rat story. The 2015; Río-Álamos et al., 2019; Tapias-Espinosa et al., 2019; funders had no role in study design, data collection and analysis, for a review see Swerdlow and Light, 2016). Hence, compared decision to publish, or preparation of the manuscript. REFERENCES Bentareha, R., Araujo, F., Ruano, D., Driscoll, P., Escorihuela, R. M., Tobeña, A., et al. (1998). Pharmacological properties of the GABAA receptor complex Aguilar, R., Escorihuela, R. 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Conflict of Interest Statement: The authors declare that the research was Behav. Proc. 151, 96–103. doi: 10.1016/j.beproc.2018.03.019 conducted in the absence of any commercial or financial relationships that could Tapias-Espinosa, C., Río-Álamos, C., Sánchez-González, A., Oliveras, I., be construed as a potential conflict of interest. Sampedro-Viana, D., Castillo-Ruiz, M. M., et al. (2019). Schizophrenia- like reduced sensorimotor gating in intact inbred and outbred rats is Copyright © 2019 Giorgi, Corda and Fernández-Teruel. This is an open-access article associated with decreased medial prefrontal cortex activity and volume. distributed under the terms of the Creative Commons Attribution License (CC BY). Neuropsychopharmacology doi: 10.1038/s41386-019-0392-x [Epub ahead of The use, distribution or reproduction in other forums is permitted, provided the print]. original author(s) and the copyright owner(s) are credited and that the original Taylor, J. R., and Horger, B. A. (1999). Enhanced responding for conditioned publication in this journal is cited, in accordance with accepted academic practice. reward produced by intra-accumbens amphetamine is potentiated after cocaine No use, distribution or reproduction is permitted which does not comply with sensitization. Psychopharmacology 142, 31–40. doi: 10.1007/s002130050859 these terms. Frontiers in Behavioral Neuroscience | www.frontiersin.org 16 July 2019 | Volume 13 | Article 145