CRF1 receptor-deficiency increases cocaine reward

Abstract

Stimulant drugs produce reward but also activate stress-responsive systems. The corticotropin-releasing factor (CRF) and the related hypothalamus-pituitary-adrenal (HPA) axis stress-responsive systems are activated by stimulant drugs. However, their role in stimulant drug-induced reward remains poorly understood. Herein, we report that CRF₁ receptor-deficient (CRF₁-/-), but not wild-type, mice show conditioned place preference (CPP) responses to a relatively low cocaine dose (5 mg/kg, i.p.). Conversely, wild-type, but not CRF₁-/-, mice display CPP responses to a relatively high cocaine dose (20 mg/kg, i.p.), indicating that CRF₁ receptor-deficiency alters the rewarding effects of cocaine. Acute pharmacological antagonism of the CRF₁ receptor by antalarmin also eliminates cocaine reward. Nevertheless, CRF₁-/- mice display higher stereotypy responses to cocaine than wild-type mice. Despite the very low plasma corticosterone concentration, CRF₁-/- mice show higher nuclear glucocorticoid receptor (GR) levels in the brain region of the hippocampus than wild-type mice. Full rescue of wild-type-like corticosterone and GR circadian rhythm and level in CRF₁-/- mice by exogenous corticosterone does not affect CRF₁ receptor-dependent cocaine reward but induces stereotypy responses to cocaine. These results indicate a critical role for the CRF₁ receptor in cocaine reward, independently of the closely related HPA axis activity.

Keywords: Cocaine; Corticotropin-releasing factor (CRF) receptor 1; Hypothalamus-pituitary-adrenal (HPA) axis; Reward; Stereotypy.