Chronic adenosine A 2A receptor blockade induces locomotor sensitization and potentiates striatal LTD IN GPR37-deficient mice.

Adenosine A(2A) receptors (A(2A)R) play a key role in modulating dopamine-dependent locomotor activity, as heralded by the sensitization of locomotor activity upon chronic A(2A)R blockade, which is associated with elevated dopamine levels and altered corticostriatal synaptic plasticity. Since the orphan receptor GPR37 has been shown to modulate A(2A)R function in vivo, we aimed to test whether the A(2A)R-mediated sensitization of locomotor activity is GPR37-dependent and involves adaptations of synaptic plasticity. To this end, we administered a selective A(2A)R antagonist, SCH58261 (1 mg/kg, i.p.), daily for 14 days, and the locomotor sensitization, striatum-dependent cued learning, and corticostriatal synaptic plasticity (i.e., long-term depression) were compared in wild-type and GPR37(-/-) mice. Notably, GPR37 deletion promoted A(2A)R-associated locomotor sensitization but not striatum-dependent cued learning revealed upon chronic SCH58261 treatment of mice. Furthermore, chronic A(2A)R blockade potentiated striatal long-term depression in corticostriatal synapses of GPR37(-/-) but not of wild-type mice, thus correlating well with neurochemical alterations of the adenosinergic system. Overall, these results revealed the importance of GPR37 regulating A(2A)R-dependent locomotor sensitization and synaptic plasticity in the basal ganglia circuitry. Open science badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at . Open Science: This manuscript was awarded with the Open Materials Badge. For more information see: