Domperidone Modulates Hippocampal D2 Expression, Facilitates Extinction, and Attenuates Morphine-Induced Conditioned Place Preference in Rats.

Peripheral dopamine D2 receptors (D2R) have been implicated in modulating reward-related behaviors; however, their role in morphine-induced conditioned place preference (CPP) remains unclear. This study evaluated whether peripheral selective D2R blockade by domperidone (DOM), with limited blood-brain barrier penetration, influences morphine-induced CPP in rats. Male Wistar rats were conditioned with morphine (5 mg/kg, subcutaneously [SC]) to induce CPP. DOM was administered intraperitoneally at 0.5, 1, and 2 mg/kg doses during acquisition, expression, and extinction phases. Behavioral CPP was assessed, and hippocampal D2R expression was measured via Western blot. During acquisition, all DOM doses significantly attenuated CPP, with 1 mg/kg being most effective (p < 0.001). In expression, 1 and 2 mg/kg doses reduced CPP (p < 0.001), with 1 mg/kg more effective. Only 1 mg/kg facilitated extinction (p < 0.01) and prevented reinstatement. Morphine has previously been shown to increase hippocampal D2R expression. In our experiments, DOM significantly decreased D2R expression in both expression and extinction phases. These results demonstrate that D2R antagonism by DOM can modulate morphine-induced CPP and hippocampal D2R expression, highlighting a potential role of peripheral dopaminergic mechanisms in opioid reward. DOM's peripheral action and efficacy suggest therapeutic potential in opioid use disorders.