GPR55 ACTIVATION MODULATES GLIAL REACTIVITY AND DOPAMINERGIC SIGNALING IN THE NUCLEUS ACCUMBENS DURING COCAINE-INDUCED LOCOMOTOR SENSITIZATION

GPR55 is an orphan G protein-coupled receptor expressed in neurons and microglial cells in reward-related brain regions, including the nucleus accumbens, suggesting a role in neuroimmune regulation. Psychostimulants such as cocaine induce neuroadaptations associated with behavioral sensitization, accompanied by microglial activation and alterations in dopamine-dependent intracellular signaling; however, the role of GPR55 in cocaine-induced microglial responses remains poorly characterized. This study aimed to determine whether GPR55 modulation affects cocaine-induced behavioral sensitization and microglial and dopaminergic alterations in the nucleus accumbens. Male C57BL/6 mice received the GPR55 agonist O-1602 or the antagonist ML-193 (2.5, 5, or 10 mg/kg, i.p.) in combination with cocaine (15 mg/kg, i.p.), administered prior to each behavioral session. Locomotor activity was assessed using a cocaine sensitization protocol. After the final session, brains were collected for immunohistochemical analysis of the nucleus accumbens core and shell. Microglial activation was evaluated by Iba-1 immunoreactivity and quantitative morphological analysis, and dopaminergic signaling was assessed by DARPP-32 immunoreactivity. GPR55 activation by O-1602 prevented cocaine-induced locomotor sensitization at doses of 2.5 and 5 mg/kg, whereas ML-193 had no effect. In the nucleus accumbens core, cocaine induced microglial activation, evidenced by increased Iba-1 immunoreactivity and an activated morphological phenotype; this effect was attenuated by O-1602, while no significant microglial changes were observed in the shell. Cocaine also increased DARPP-32 immunoreactivity in the nucleus accumbens core, which was prevented by GPR55 activation. These findings indicate that GPR55 modulates cocaine-induced behavioral sensitization through regulation of microglial activation and dopaminergic signaling in the nucleus accumbens.