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Local inactivation of Gpr88 in the nucleus accumbens attenuates behavioral deficits elicited by the neonatal administration of phencyclidine in rats

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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.

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Acknowledgements

The LV vectors were generated and produced in the vectorology platform of the ICM. LCM experiment was carried out at the ProfilExpert Platform of Lyon. Behavioral studies were performed at the animal facility behavioral platform of the ICM.

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Correspondence to R Meloni.

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LLB and Drs NFB, ADT, PR, JM, RM declare no potential conflict of interest. MI was supported by a Grant from the Institut de Recherche Servier. Drs CMlC and MJM are full-time employees of the Institut de Recherche Servier. They have no other interests to declare.

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Ingallinesi, M., Le Bouil, L., Faucon Biguet, N. et al. Local inactivation of Gpr88 in the nucleus accumbens attenuates behavioral deficits elicited by the neonatal administration of phencyclidine in rats. Mol Psychiatry 20, 951–958 (2015). https://doi.org/10.1038/mp.2014.92

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