Agonist and antagonist effects of aripiprazole on D<inf>2</inf>-like receptors controlling rat brain dopamine synthesis depend on the dopaminergic tone
Ma, Guofen (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Raivio, Noora (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Sabrià i Pau, Josefa (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Ortiz de Pablo, Jordi (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Data:	2014
Resum:	Background: The atypical antipsychotic drug aripiprazole binds with high affinity to a number of G protein coupled receptors, including dopamine D2 receptors, where its degree of efficacy as a partial agonist remains controversial. Methods: We examined the properties of aripiprazole at D2-like autoreceptors by monitoring the changes of dopamine synthesis in adult rat brain striatal minces incubated ex vivo. The effects of the dopaminergic tone on the properties of aripiprazole were assayed by comparing a basal condition (2 mM K+, low dopaminergic tone) and a stimulated condition (15 mM K+ where dopamine release mimics a relatively higher dopaminergic tone). We also used 2 reference compounds: quinpirole showed a clear agonistic activity and preclamol (S-(-)-PPP) showed partial agonism under both basal and stimulated conditions. Results: Aripiprazole under the basal condition acted as an agonist at D2-like autoreceptors and fully activated them at about 10 nM, inhibiting dopamine synthesis similarly to quinpirole. Higher concentrations of aripiprazole had effects not restricted to D2-like autoreceptor activation. Under the stimulated (15 mM K+) condition, nanomolar concentrations of aripiprazole failed to decrease dopamine synthesis but could totally block the effect of quinpirole. Conclusions: Under high dopaminergic tone, aripiprazole acts as a D2-like autoreceptor antagonist rather than as an agonist. These data show that, ex vivo, alteration of dopaminergic tone by depolarization affects the actions of aripiprazole on D2-like autoreceptors. Such unusual effects were not seen with the typical partial agonist preclamol and are consistent with the hypothesis that aripiprazole is a functionally selective D2R ligand.
Ajuts:	Ministerio de Educación y Ciencia SAF2006-08240 Ministerio de Educación y Ciencia SAF2009-12510
Nota:	Supported by grants SAF2006-08240, SAF2009-12510, and Red de Trastornos Adictivos RD06/0001/0015. G.F.M. was the recipient of a CSC fellowship.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Schizophrenia ; Striatum ; Intrinsic efficacy ; Intrinsic activity ; GPCR
Publicat a:	International journal of neuropsychopharmacology, Vol. 18, Núm. 4 (february 2015) , p. 1-9, ISSN 1469-5111

Adreça alternativa: https://academic.oup.com/ijnp/article/18/4/pyu046/663680
DOI: 10.1093/ijnp/pyu046
PMID: 25522390

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