Gpr88 deletion impacts motivational control independently of striatal dopamine function

Background: Disrupted motivational control is a common, but poorly treated, feature of psychiatric disorders. Aberrant mesolimbic dopamine signalling is implicated in motivational symptoms, however direct manipulations to these pathways have yielded suboptimal therapeutic effects. GPR88 is an orphan G protein-coupled receptor highly expressed in the striatum on medium spiny neurons, and therefore well-placed to modulate striatal signalling. While the phenotype of Gpr88 knockout mice supports a disruption of motivational pathways, it is unclear whether GPR88 is involved in reward valuation and/or effort-based decision making in a sex-dependent manner, and if this involves altered dopamine function. Methods : In male and female Gpr88 knockout mice, we used touchscreen-based progressive ratio, with and without reward devaluation, and effort-related choice tasks to assess motivation and cost/benefit decision making, respectively. To explore whether these motivational behaviours were related to altered striatal dopamine, we quantified expression of dopamine-related genes and/or proteins, and used [18F]DOPA PET and GTPγ[35S] binding to assess pre- and postsynaptic dopamine function, respectively. Results : We show that male and female Gpr88 knockout mice display greater motivational drive than wild-type mice, which was maintained following reward devaluation. Further, we show that cost/benefit decision making is impaired in male, but not female, Gpr88 knockout mice. Surprisingly, we found that Gpr88 deletion had no effect on striatal dopamine by any of the measures assessed. Conclusion : Our results highlight that GPR88 regulates motivational control of behaviour through a dopaminergic-independent mechanism, providing further support for GPR88 as target for mood symptoms in psychiatric disorders. ### Competing Interest Statement This work was partially funded by Les Laboratoires Servier. CMLC is a full-time employee of Les Laboratoires Servier. All other authors declare no competing financial interests.