GPR88 is an orphan G protein-coupled receptor highly expressed in striatal D1R and D2R-expressing medium spiny neurons. This receptor is involved in activity and motor responses, and we previously showed that this receptor also regulates anxiety-like behaviors. To determine whether GPR88 in D2R-expressing neurons contributes to this emotional phenotype, we generated conditional Gpr88 knockout mice using A2AR-Cre-driven recombination, and compared anxiety-related responses in both total and A2AR-Gpr88 KO mice. A2AR-Gpr88 KO mice showed a selective reduction of Gpr88 mRNA in D2R- but not D1R-expressing neurons. These mutant mice showed increased locomotor activity and decreased anxiety-like behaviors in light dark and elevated plus maze tests. These phenotypes were superimposable to those observed in total Gpr88 KO mice, demonstrating that the previously reported anxiogenic activity of GPR88 operates at the level of A2AR-expressing neurons. Further, A2AR-Gpr88 KO mice showed no change in novelty preference and novelty-suppressed feeding, while these responses were increased and decreased, respectively, in the total Gpr88 KO mice. Also, A2AR-Gpr88 KO mice showed intact fear conditioning, while the fear responses were decreased in total Gpr88 KO. We therefore also show for the first time that GPR88 activity regulates approach behaviors and conditional fear, however these behaviors do not seem mediated by receptors in A2AR-neurons. We conclude that Gpr88 expressed in A2AR neurons enhances ethological anxiety-like behaviors without affecting conflict anxiety and fear responses.
Significance Statement: GPR88, a striatal enriched orphan G protein-coupled receptor has been implicated in regulation of anxiety-like behaviors. In the striatum, GPR88 is most abundant in both medium spiny neurons expressing dopamine D1 receptors and dopamine D2 receptors. To evaluate the contribution of GPR88 in D2R-neurons, we compared anxiety-like and fear-related behavioral responses of newly generated conditional A2AR-Gpr88 mice, with those of total Gpr88 knockout animals. Our data show that GPR88 expressed in A2AR -neurons increases ethological anxiety-like behaviors without affecting conflict anxiety and fear responses. These results represent a first step towards understanding circuit mechanisms underlying GPR88 function in the brain. Future studies will evaluate the role of GPR88 in D1R-neurons.
The authors report no biomedical financial interests or potential conflicts of interest.
National Institute of Health [NIH-NIAAA #16658].