Lack of behavioral sensitization after repeated exposure to THC in mice and comparison to methamphetamine

Rationale Recent evidence has provided support for the incentive-sensitization model of addiction, where repeated stimulation of neural reward circuits leads to a long-lasting sensitization of mesolimbic dopaminergic activity. This phenomenon has been demonstrated with many drugs of abuse, most often by measuring progressively increased activating effects of drugs on locomotor activity, thought to reflect an underlying neural sensitization. Whether cannabinoids, and in particular Delta 9-tetrahydrocannabinol (THC), produce similar effects in this model is somewhat controversial, with mixed evidence in the literature. Objectives These experiments were conducted to determine whether behavioral sensitization could be established in mice after repeated exposure to THC. Sensitization to repeated methamphetamine treatment was used as a positive control. Methods The effects of acute and repeated intermittent (every 3-4 days) treatment with THC or methamphetamine on locomotor activity were determined in Institute of Cancer Research (ICR) mice. Additional experiments with THC employed a dosing regimen that increased the number of injections, controlled for behavioral tolerance, examined different aspects of behavior, and used a different species (Sprague-Dawley rats). Results Both methamphetamine and THC acutely increased activity. A robust dose-dependent sensitization was observed after intermittent treatment with methamphetamine but not with THC. Additionally, no evidence for behavioral sensitization to the effects of THC was found with any of the various protocols. Conclusions These data suggest that repeated THC treatment is less likely to produce behavioral sensitization than are other drugs of abuse. It appears that this phenomenon may only occur under very particular conditions, which raises doubts about its relevance to chronic cannabis users.