Antagonism of ∆⁹-THC induced behavioral effects by rimonabant: time course studies in rats

The objective was to examine the time course of the cannabinoid 1 receptor antagonist/inverse agonist rimonabant's ability to antagonize in vivo cannabinergic agonist effects. We used two behavioral procedures sensitive to the effects of ∆⁹-tetrahydrocannabinol (∆⁹-THC): rat drug discrimination (EXP-1) and suppression of fixed-ratio responding (FR) for food reinforcement (EXP-2). Two training doses of ∆⁹-THC (1.8 and 3 mg/kg) served as discriminative cues in two groups discriminating ∆⁹-THC from vehicle; injections were i.p. 20 min before session onset. Tests assessed the dose-response functions of ∆⁹-THC and the time course for rimonabant in its ability to block the discriminative stimulus effects of ∆⁹-THC. For antagonism testing, the training doses of ∆⁹-THC were used and the rimonabant dose was 1mg/kg. Tests were 20, 60, 120, and 240 min post rimonabant administration; ∆⁹-THC was always administered 20 min prior to testing. For EXP-2, only one response lever was activated and every 10th (FR-10) press on that lever resulted in food delivery. Once the response rate stabilized, tests occurred with ∆⁹-THC, rimonabant and combinations of the drugs. The ED(50) estimates for the dose-response functions were 0.38 (±0.28-0.51) and 0.50 (±0.40-0.63) mg/kg for the training doses of 1.8 and 3 mg/kg ∆⁹-THC, respectively. The time course studies suggested functional half-life estimates of 128.4 (±95.7-172.2) and 98.4 (±64.2-150.7) min by rimonabant for the two groups in EXP-1, respectively. Similarly, the functional half-life of rimonabant was 118.9 (±66.1-213.9) min in EXP-2. Thus, antagonism of ∆⁹-THC by rimonabant is relatively short lasting.