Long‐term effects of iloperidone on cerebral dopamine receptor subtypes

The atypical antipsychotic drug iloperidone has high affinity for a wide range of neurotransmitter receptors, including dopaminergic (DA), serotonergic, and adrenergic receptors. We examined the long‐term effects of multiple doses of iloperidone on DA D1, D2, D3, and D4 receptor subtypes. Sprague‐Dawley adult rats (n = 8/group) received daily intraperitoneal injections of iloperiodone (0.5, 1, or 5 mg/kg) or vehicle for 4 weeks. Receptor autoradiography quantified the levels of DA receptors in medial prefrontal cortex (MPC), dorsolateral frontal cortex (DFC), caudate putamen (CPu), nucleus accumbens (NAc), and hippocampus (HIP). Four weeks of iloperidone treatment at 5 mg/kg significantly increased D1 receptors in NAc (36%) and CPu (38%). Iloperidone (1.5 and 5 mg/kg) dose‐dependently increased D2 receptors in MPC (37 and 47%) and HIP (32 and 40%). Only the high dose of iloperidone (5 mg/kg) increased D2 receptors in NAc (39%) and CPu (38%). Repeated treatment with iloperidone (1.5 and 5 mg/kg) increased D4 receptors in the NAc (39 and 78%), CPu (42 and 83%) and HIP (54 and 72%). The three doses of iloperidone failed to alter D3 receptors in the brain regions examined in this study. These results suggest that iloperidone exerts region‐ and dose‐specific effects on forebrain DA receptor subtypes, which may contribute to its therapeutic benefits in improving the positive and negative symptoms of schizophrenia with minimal extrapyramidal side effects. Using receptor autoradiography, the authors found that chronic treatment with the atypical antipsychotic drug iloperidone produced region‐ and dose‐specific effects on forebrain dopamine receptor subtypes, which may account for iloperidone’s unique psychopharmacological profile.