G protein-coupled receptors (GPCRs) are the most miscellaneous and major family of mammalian transmembrane proteins and share a common seven-transmembrane configuration. Whereas these receptors can be activated by hormones, neurotransmitters, odorants, light, pheromones, peptides, organic compounds, and eicosanoids, there are a large numbers of GPCRs for which no endogenous ligands have been identified to date. These receptors are thus named orphan GPCRs. GPR52 is a type of orphan GPCRs which are coupled to Gs proteins, resulting in increase in intracellular cAMP level. Whereas GPR52 has been related to a variety of neurological disorders including schizophrenia, cognitive impairment, Huntington’s disease and substance abuses, its underpinning cellular and molecular mechanisms on neuronal activity have not been determined. As high densities of GPR52 are expressed in the nucleus accumbens, we probed the effects of GPR52 on the excitability of medium spiny neurons (MSNs), the principal neuronal types in the nucleus accumbens using whole-cell patch-clamp recordings in brain slices. Our results showed that bath application of the selective GPR52 agonists, TP-024 (1 μM) and PW07875 (1 μM) depolarized MSNs, suggesting that activation of GPR52 facilitates the excitability of MSNs in the nucleus accumbens. To identify the ionic mechanisms involved in GPR52-mediated depolarization of MSNs, we constructed the voltage-current (V-I) relationship of TP-024-induced net currents. The examined MSNs showed a V-I relationship belonging to cation channels and 9 cells displayed a V-I curve resembling the inward rectifier K+ channels. Our results suggest that multiple ionic mechanisms are involved in GPR52 excitation of MSNs in the nucleus accumbens.