Deletion Impacts Motivational Control Without Overt Disruptions to Striatal Dopamine.

Background: Disrupted motivational control is a common-but poorly treated-feature of psychiatric disorders, arising via aberrant mesolimbic dopaminergic signaling. GPR88 is an orphan G protein-coupled receptor that is highly expressed in the striatum and therefore well placed to modulate disrupted signaling. While the phenotype of knockout mice suggests a role in motivational pathways, it is unclear whether GPR88 is involved in reward valuation and/or effort-based decision making in a sex-dependent manner and whether this involves altered dopamine function.

Methods: In male and female 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 behaviors were related to alterations in the striatal dopamine system, we quantified expression of dopamine-related genes and/or proteins and used [F]DOPA positron emission tomography and GTPγ[S] binding to assess presynaptic and postsynaptic dopamine function, respectively.

Results: We showed that male and female knockout mice displayed greater motivational drive than wild-type mice, which was maintained following reward devaluation. Furthermore, we showed that cost/benefit decision making was impaired in male, but not female, knockout mice. Surprisingly, we found that deletion had no effect on striatal dopamine by any of the measures assessed.

Conclusions: Our results highlight that GPR88 regulates motivational control but that disruption of such behaviors following deletion occurs independently of gross perturbations to striatal dopamine at a gene, protein, or functional level. This work provides further insights into GPR88 as a drug target for motivational disorders.