The mGlu5 receptor negative allosteric modulator mavoglurant reduces escalated cocaine self-administration in male and female rats

Abstract Rationale Cocaine use disorder (CUD) is a brain disorder for which there is no Food and Drug Administration-approved pharmacological treatment. Evidence suggests that glutamate and metabotropic glutamate receptor subtype 5 (mGlu5) play critical roles in synaptic plasticity, neuronal development, and psychiatric disorders. Objective In the present study, we tested the hypothesis that the mGlu5 receptor is functionally involved in intravenous cocaine self-administration and assessed the effects of sex and cocaine exposure history. Methods We used a preclinical model of CUD in rats that were allowed long access (LgA; 6 h/day) or short access (ShA; 1 h/day) to intravenous cocaine (750 µg/kg/infusion 0.1 ml) self-administration. Rats received acute intraperitoneal or oral administration of the mGlu5 receptor negative allosteric modulator mavoglurant (1, 3, and 10 mg/kg) or vehicle. Results Both intraperitoneal and oral mavoglurant administration dose-dependently reduced intravenous cocaine self-administration in the first hour and in the entire 6 h session in rats in the LgA group, with no effect on locomotion. In the ShA group, mavoglurant decreased locomotion but had no effects on cocaine self-administration. We did not observe significant sex × treatment interactions. Conclusions These findings suggest that the mGlu5 receptor is involved in escalated cocaine self-administration. These findings support the development of clinical trials of mavoglurant to evaluate its potential therapeutic benefits for CUD.