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.

Mice Lacking GPR88 Show Motor Deficit, Improved Spatial Learning, and Low Anxiety Reversed by Delta Opioid Antagonist

“…Whether molecular and behavioral phenotypes observed in Gpr88 knockout mice arise from developmental compensations or lack of tonic GPR88 receptor activity in adult mutant mice, or both, deserves further investigation. In a previous report, virally mediated inactivation of Gpr88 in the NAc of adult rats reduced amphetamine-induced hyperlocomotion (12), demonstrating a tonic role of GPR88 activity for this particular behavior. Future studies will involve time-controlled genetic inactivation, as well as pharmacology with existing (10) or novel GPR88 drugs to tease out developmental from adult GPR88 activities.…”

“…Gpr88 gene is detected in projection medium spiny neurons (MSNs) of both striatonigral and striatopallidal pathways, under the control of corticostriatal inputs (3). At present, only one synthetic agonist has been reported (10, 11) and functional studies of GPR88 have used genetic approaches (2, 12, 13). The analysis of mice lacking the Gpr88 gene demonstrates an essential role for GPR88 receptors in dopamine neurotransmission and striatal physiology.…”

“…In addition, behavioral deficits evocative of striatal dysfunction were reported, including increased apomorphine and amphetamine effects on locomotor activity (2), or reduced motor coordination and altered cue-based learning (13). Finally, amphetamine locomotor effects were inhibited by local silencing of Gpr88 in the NAc (12). …”

Developmental and adult expression patterns of the G‐protein‐coupled receptor GPR88 in the rat: Establishment of a dual nuclear–cytoplasmic localization

“…A delta opioid antagonist could reverse most of these behavioral alterations. Finally, local inactivation of GPR88 in the nucleus accumbens overrode behavioral deficits caused by the neonatal administration of phencyclidine in rats (Ingallinesi et al, ).…”

GPR88 in A2A receptor‐expressing neurons modulates locomotor response to dopamine agonists but not sensorimotor gating

“…Accordingly, both PPI deficits and apomorphine-induced stereotypies could be reverted by typical (haloperidol) and atypical (risperidone) neuroleptic treatments suggesting that altered GPR88 signalling may contribute to some aspects of schizophrenia syndrome (Logue et al, 2009). By contrast, Ingallinesi et al (2015) showed that local silencing of GPR88 in the ventral striatum (nucleus accumbens) produces no behavioural alterations in normal rats, but attenuates the schizophrenia-related phenotypes (amphetamine-induced locomotor hyperactivity and social novelty discrimination deficit) elicited by neonatal exposure to phencyclidine. Together, these findings highlight the complex role of GPR88 in the control of striatal function and suggest that dysfunction of GPR88 signalling may contribute to a range of neuropsychiatric disorders that involve abnormal motor, cognitive and emotional behaviour.…”