Study of cannabinoid dependence in animals.

Different animal models have been used to clarify the consequences of chronic exposure to cannabinoid agonists and their abuse liability. Following the chronic administration of cannabinoids, tolerance develops to most of their pharmacological effects. The development of cannabinoid tolerance is particularly rapid, and seems to be due to pharmacodynamic events. A cross-tolerance among different exogenous cannabinoid agonists has been reported. Somatic signs of spontaneous withdrawal have not been reported after chronic Delta(9)-tetrahydrocannabinol (THC) treatment, but were observed after chronic treatment with the cannabinoid agonist WIN-55,212-2. The administration of the CB(1) cannabinoid antagonist SR141716A in animals chronically treated with THC and other cannabinoid agonists precipitated somatic manifestations of withdrawal. The potential ability of anandamide to induce physical dependence has not been clarified. Subjective drug effects of cannabinoids have been reported by drug discrimination studies, which show cross discrimination among different natural and synthetic agonists. The rewarding effects of cannabinoids have been revealed by using several paradigms: place conditioning, intracranial self-stimulation, and self-administration. Cannabinoids have been reported to lower intracranial self-stimulation thresholds in rats. However, particular experimental conditions are required to induce conditioned place preference with cannabinoids. Numerous studies have shown that THC is unable to induce a self-administration behaviour in animals. However, WIN-55,212-2 was intravenously self-administered in mice, and monkeys that had a previous history of cocaine self-administration also self-administered THC. The mesolimbic dopaminergic system seems to be the substrate for the rewarding properties of cannabinoids.