AbstractBackgroundPrevious studies suggest the possible effect of risperidone on brain reward system and D1 and D2 dopamine receptors’ involvement in morphine‐induced conditioned place preference (CPP).AimsThe present study was designed to investigate the effect of risperidone as an atypical antipsychotic drug on morphine‐induced CPP and D2‐like dopamine receptor gene expression in rat.Materials and MethodsAn unbiased CPP paradigm was used to study the effect of risperidone. Intraperitoneal (i.p.) injection of risperidone (1, 2, and 4 mg/kg) was performed 30 min before the morphine (10 mg/kg, i.p.) injection and just after the rat was placed in the CPP box. The open field test was used to assay the locomotor activity of animal. The gene expression of D2 dopamine receptor in hippocampus was measured by real‐time PCR technique. The hippocampi of rats were also used for histology evaluation.ResultsMorphine‐produced (10 mg/kg) CPP and morphine‐induced CPP were reversed only by the administration of a low dose of risperidone (1 mg/kg). Low dose of risperidone (1 mg/kg) showed no effect on locomotor activity but a higher dose of risperidone (2 and 4 mg/kg) decreased locomotor activity. Real‐time PCR data analysis revealed that the gene expression of D2 dopamine receptor had significant difference between morphine and a 1 mg/kg dose of risperidone. Moreover, in histological evaluation, apoptosis was observed in the morphine group, whereas there was no evidence of apoptosis in the risperidone‐treated groups.ConclusionOur results suggest that risperidone (1 mg/kg) reverses the morphine‐induced CPP and may reduce the rewarding properties of morphine. It is also demonstrated that risperidone decreases the expression of D2 receptor in rat hippocampus. Therefore, risperidone can be considered potential adjunct therapy in morphine dependence.