Evaluation of the 5-HT2C receptor drugs RO 60-0175, WAY 161503 and mirtazepine in a preclinical model of comorbidity of cocaine addiction and depression

Abstract

Abstract Epidemiological data indicate a high rate of comorbidity of depression and cocaine use disorder (CUD). The role of 5-HT2C receptors in the mechanisms responsible for the coexistence of CUD and depression has not been investigated. Here, we combined bilateral olfactory bulbectomy (OBX), an animal model of depression, with intravenous cocaine self-administration and extinction/reinstatement in male rats to investigate two 5-HT2C receptor agonists (Ro 60–0175 (RO) and WAY 161503 (WAY)) and the 5-HT2C-receptor preferring antagonist mirtazapine (MIR; an antidepressant), with the goal of determining whether these drugs alter cocaine-induced reinforcement and seeking behaviors. Additionally, neurochemical analyses following cocaine self-administration and its abstinence period in the brain structures in OBX rats and SHAM-operated controls were performed. Acute administration of RO reduced, while WAY non-significantly attenuated cocaine reinforcement in OBX and SHAM rats. Moreover, RO or WAY protected against cocaine-seeking behavior after acute repeated drug administration during extinction training in OBX and SHAM rats. By contrast, acutely administered MIR did not alter cocaine reinforcement in both rat phenotypes, while acute (but not repeated) pretreatment reduced cocaine seeking in OBX and SHAM rats. In neurochemical analyses, cocaine reinforcement increased 5-HT2C receptor levels in the ventral hippocampus; this effect was enhanced by preexisting depression-like phenotype. The 10-daily cocaine abstinence from self-administration reduced 5-HT2C receptor expression in the dorsolateral striatum but coexistence of depression and CUD enhanced local receptor expression. The present study supports further development of pharmacological strategies with drugs targeting the 5-HT2C receptor for the treatment of comorbid depression and CUD.