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.