Role of GABA-active neurosteroids in the efficacy of metyrapone against cocaine addiction

•The rapid actions and pharmacological mechanisms of metyrapone were investigated in a rat model of cocaine addiction.•Metyrapone decreased cocaine self-administration in a dose-dependent manner.•Bicuculline, a GABAA receptor antagonist, partially attenuates metyrapone's effects on cocaine self-administration.•Finasteride, a 5alpha-reductase inhibitor, affected cocaine self-administration as well.•These results suggest that metyrapone may act via GABA-active steroid metabolites to decrease cocaine self-administration. Previous research has demonstrated a complicated role for stress and HPA axis activation in potentiating various cocaine-related behaviors in preclinical models of drug dependence. However, the investigation of several antiglucocorticoid therapies has yielded equivocal results in reducing cocaine-related behaviors, possibly because of varying mechanisms of actions. Specifically, research suggests that metyrapone (a corticosterone synthesis inhibitor) may reduce cocaine self-administration in rats via a nongenomic, extra-adrenal mechanism without altering plasma corticosterone. In the current experiments, male rats were trained to self-administer cocaine infusions and food pellets in a multiple, alternating schedule of reinforcement. Metyrapone pretreatment dose-dependently decreased cocaine self-administration as demonstrated previously. Pharmacological inhibition of neurosteroid production by finasteride had significant effects on cocaine self-administration, regardless of metyrapone pretreatment. However, metyrapone's effects on cocaine self-administration were significantly attenuated with bicuculline pretreatment, suggesting a role for GABA-active neurosteroids in cocaine-reinforced behaviors. In vitro binding data also confirmed that metyrapone does not selectively bind to GABA-related proteins. The results of these experiments support the hypothesis that metyrapone may increase neurosteroidogenesis to produce effects on cocaine-related behaviors.