title: Local inactivation of Gpr88 in the nucleus accumbens attenuates behavioral deficits elicited by the neonatal administration of phencyclidine in rats.
abstract: Gpr88, an orphan G-protein-coupled receptor, is highly and almost exclusively expressed in the medium spiny projection neurons of the striatum, and may thus participate in the control of motor functions and cognitive processing that are impaired in neuropsychiatric disorders such as Parkinson's disease or schizophrenia (SZ). This study investigated the relevance of Gpr88 to SZ-associated behavior by knocking down Gpr88 gene expression in the ventral striatum (nucleus accumbens) in a neurodevelopmental rat model of SZ, generated by neonatal treatment with phencyclidine (PCP). In this model, we compared the effects of the local inactivation in the adult animal of the expression of Gpr88 and of Drd2, a gene strongly implicated in the etiology of SZ and coding for the dopamine receptor type 2 (D2). To inactivate specifically Gpr88 and D2 expression, we used the lentiviral vector-mediated microRNA silencing strategy. The neonatal PCP treatment induced in the adult rat hyperlocomotion in response to amphetamine (Amph) and social novelty discrimination (SND) deficits. The inactivation of D2 did not modify the locomotor response to Amph or the cognitive deficits induced by PCP, whereas the silencing of Gpr88 inhibited the Amph-induced hyperlocomotion and reduced the impairment of SND elicited by neonatal exposure to PCP. These observations suggest a role for Gpr88 in the regulation of cognitive and motor functions, and support its relevance to the pathophysiology and treatment of SZ and other disorders involving dysfunction of the accumbens-striatal complex.
authors.affiliation: Biotechnology and Biotherapy Laboratory, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, CHU Pitié-Salpêtrière, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Ingallinesi
authors.affiliation: Biotechnology and Biotherapy Laboratory, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, CHU Pitié-Salpêtrière, Paris, France.
authors.forename: L
authors.initials: L
authors.lastname: Le Bouil
authors.affiliation: Biotechnology and Biotherapy Laboratory, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, CHU Pitié-Salpêtrière, Paris, France.
authors.forename: N Faucon
authors.initials: NF
authors.lastname: Biguet
authors.affiliation: Biotechnology and Biotherapy Laboratory, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, CHU Pitié-Salpêtrière, Paris, France.
authors.forename: A Do
authors.initials: AD
authors.lastname: Thi
authors.affiliation: Pole of Therapeutic Innovation in Neuropsychiatry, Institut de Recherches Servier (IDRS), Croissy-sur-Seine, France.
authors.forename: C
authors.initials: C
authors.lastname: Mannoury la Cour
authors.affiliation: Pole of Therapeutic Innovation in Neuropsychiatry, Institut de Recherches Servier (IDRS), Croissy-sur-Seine, France.
authors.forename: M J
authors.initials: MJ
authors.lastname: Millan
authors.affiliation: Biotechnology and Biotherapy Laboratory, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, CHU Pitié-Salpêtrière, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Ravassard
authors.affiliation: 1] Biotechnology and Biotherapy Laboratory, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, CHU Pitié-Salpêtrière, Paris, France [2] Department of Neurological Surgery, University of California San Francisco (UCSF), San Francisco, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Mallet
authors.affiliation: Biotechnology and Biotherapy Laboratory, Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, CHU Pitié-Salpêtrière, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Meloni
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003072:Cognition Disorders / Q000378:metabolism; D004192:Discrimination, Psychological / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D008297:Male; D035683:MicroRNAs; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D010622:Phencyclidine; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000235:genetics; D012559:Schizophrenia / Q000378:metabolism*; D012919:Social Behavior
chemical_list: D000697:Central Nervous System Stimulants; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C000606984:Gpr88 protein, rat; D035683:MicroRNAs; C497930:Ppp1r1b protein, rat; D043562:Receptors, G-Protein-Coupled; D000661:Amphetamine; D010622:Phencyclidine