Heroin-induced neuroadaptations of CB1 receptors and their involvement in conditioned place preference.

RATIONALE: Chronic opioid use leads to long-term dysregulation of the systems related to reward, pain and stress. In recent years, much attention has been given to the role of endocannabinoid CB1 receptors in opioid-driven behaviors. However, neuroadaptations of these receptors following opioid exposure is less clear. OBJECTIVES: In this study, we systematically assessed CB1 receptor protein expression within the cortico-mesolimbic-basal ganglia circuit in rats with a history of heroin exposure and assessed the involvement of CB1 receptors in heroin conditioned place preference (CPP). RESULTS: (1) During naloxone-precipitated withdrawal, heroin-treated rats showed significantly more withdrawal signs including rapid weight loss, wet dog shakes, abnormal posture, genital grooming and urination than saline control rats. Although heroin-treated rats scored higher on criteria pertaining to vocalization, defecation, jumping and profuse salivation than did saline-treated rats, these trends did not reach statistical significance. (2) Using Western Blotting, we found that there were significant decreases in CB1 receptor protein expression in the nucleus accumbens (NAc), hypothalamus (Hypoth), substantia nigra (SN) and pedunculopontine nucleus (PPT), but no changes in this protein were detected in the prefrontal cortex, insula, dorsal striatum, medial/lateral septi, amygdala, dorsal hippocampus, ventral tegmental area and lateral tegmental nucleus. 3). Intracranial microinjections of AM251 (a CB1 receptor antagonist) into the NAc, SN, Hypoth or PPT caused significant and dose-dependent reductions in heroin CPP. CONCLUSIONS: These data suggest that CB1 receptors undergo region-specific neuroadaptation following chronic heroin exposure and are involved in heroin CPP.