Precipitated and spontaneous withdrawal in rats tolerant to anandamide

Rationale: There is evidence that cannabinoids cause tolerance and physical dependence in humans and animals. Objectives: The aim of this work was to study whether the endogenous ligand for the cannabinoid receptor, arachidonylethanolamide (anandamide), induced behavioral tolerance and physical dependence in rats. Methods: Rats were injected with anandamide (20 mg/kg IF) daily for 2 weeks. To assess tolerance, on days 1, 8 and 15 of treatment rats were observed and behavior was tested. Two common methods were employed to assess physical dependence: interruption of anandamide dosing and vehicle substitution or administration of the cannabinoid CB1 receptor antagonist SR141716A (3 mg/kg IF). Results: Full or partial tolerance developed to the classical behavioral effects elicited by the cannabinoids: hypothermia, catalepsy, hypomotility, decrease in stereotypic activity (rearing and grooming) and hindlimb splaying. No tolerance to anandamide was observed for reduced defecation. An abstinence syndrome appeared after abrupt cessation of cannabinoid intake and after withdrawal precipitated by SR141716A; the withdrawal signs were scratching, licking and biting, eating of feces, ptosis, arched back, wet dog shakes, head shakes, myoclonic spasms, writhing, forepaw fluttering, teeth chattering and piloerection. Conclusions: These findings indicate that the endogenous cannabinoid ligand, administered exogenously, induces both tolerance and physical dependence in rats.