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

Abstract

Background GPR88 is an orphan G protein coupled receptor (GPCR) highly enriched in the striatum, and previous studies have focused on GPR88 function in striatal physiology. The receptor is also expressed in other brain areas and here we examined whether GPR88 function extends beyond striatal-mediated responses. Methods We created Gpr88 knockout mice and examined both striatal and extra-striatal regions at molecular and cellular levels. We also tested striatum, hippocampus- and amygdala-dependent behaviors in Gpr88−/− mice using extensive behavioral testing. Results We found increased G protein coupling for delta (DOR) and mu opioid, but not other Gi/o coupled receptors, in the striatum of Gpr88 knockout mice. We also found modifications in gene transcription, dopamine and serotonin contents, and dendritic morphology inside and outside the striatum. Behavioral testing confirmed striatal deficits (hyperactivity, stereotypies, motor impairment in rotarod). In addition, mutant mice performed better in spatial tasks dependent on hippocampus (Y-maze, novel object recognition, dual solution cross-maze) and also showed markedly reduced levels of anxiety (elevated plus maze, marble burying, novelty suppressed feeding). Strikingly, chronic blockade of DOR using naltrindole partially improved motor coordination, and normalized spatial navigation and anxiety of Gpr88−/− mice. Conclusion We demonstrate that GPR88 is implicated in a large repertoire of behavioral responses that engage motor activity, spatial learning and emotional processing. Our data also reveal functional antagonism between GPR88 and DOR activities in vivo. The therapeutic potential of GPR88 therefore extends to cognitive and anxiety disorders, possibly in interaction with other receptor systems.

Development and validation of a high-throughput calcium mobilization assay for the orphan receptor GPR88

“…In a different study, GPR88-deficient mice exhibited increased locomotion, poor motor coordination and impaired cue-based learning, which could be normalized by targeted viral expression of the receptor in striatal MSNs [8]. A recent study also linked GPR88 to anxiety disorders, as the GPR88-knockout mice exhibited low anxiety compared to wild-type animals [13]. …”

Effect of Substitution on the Aniline Moiety of the GPR88 Agonist 2-PCCA: Synthesis, Structure–Activity Relationships, and Molecular Modeling Studies

“…Interestingly, a recent study showed that the GPR88-deficient mice performed better in spatial tasks and reduced levels of anxiety, indicating GPR88 may also play a role in cognitive and anxiety disorders. 11 …”

Design, synthesis and pharmacological evaluation of 4-hydroxyphenylglycine and 4-hydroxyphenylglycinol derivatives as GPR88 agonists

“…14 Given its favorable calculated physiochemical properties (clogP = 4.53, TPSA = 64.35, logBB = −0.12) 15–17 and GPR88-specific activity in the striatum, 11 2-AMPP is a promising lead for further optimization to probe GPR88 in vivo functions. In order to gain the SAR information of 2-AMPP for high potency, we have synthesized a series of analogues with structural modifications at sites A and B (Figure 1) and evaluated their agonist activity at GPR88.…”

“…4–8 Genetically-modified mice that lack GPR88 expression exhibit enhanced response to dopaminergic agonists and altered performance in models relevant to schizophrenia and anxiety, indicating that GPR88 may have a potential therapeutic role in treating these CNS disorders. 9–11 …”

“…14 Later, 2 was shown to elicit strong [ 35 S]-GTPγS binding (EC 50 = 940 nM) in mice striatal membranes but was ineffective in the samples from the GPR88 knockout mice, demonstrating the compound is GPR88-specific in the striatum. 11 Early structure-activity relationship (SAR) studies of 2 suggest that the amine group can be replaced by a hydroxyl group to give phenylglycinol 3 without altering GPR88 potency, whereas the substitutions on the amide cap seem to have a profound effect on the activity. In this paper, we designed and synthesized a new series of 4-hydroxyphenylglycine and 4-hydroxyphenylglycinol derivatives with structural modifications at sites A and B (Figure 1) in order to determine receptor tolerances at each site and enhance the potency for GPR88.…”