Chronic WIN55,212-2 elicits sustained and conditioned increases in intracranial self-stimulation thresholds in the rat

The present study sought to examine whether repeated administration of the CB1 receptor agonist WIN55,212-2 affected intracranial self-stimulation (ICSS) behavior and induced phenomena of tolerance or sensitization, similar to typical addictive drugs. Rats received intraperitoneal injections of vehicle for 5 days, vehicle or WIN55,212-2 (0.1, 0.3 or 1 mg/kg) for 20 subsequent days, and vehicle for 5 additional days. Thresholds for ICSS were measured before and after each injection. The initial five injections of vehicle did not affect ICSS thresholds. WIN55,212-2 (1 mg/kg) significantly increased ICSS thresholds from the first day of administration, an effect that remained stable across the subsequent days of administration. During the 5 additional days, where WIN55,212-2 was substituted with vehicle, rats demonstrated a conditioned increase in postinjection thresholds that was significant the first 3 days of this period. These findings indicate that repeated WIN55,212-2 administration elicited a sustained increase in ICSS, i.e., phenomena of tolerance or sensitization were not observed. The present data demonstrate cannabinoid-predictive stimuli that may gain affective salience and play an important role in maintaining cannabinoid administration.