The general goal of this R21 application is to develop and characterize a novel drug discrimination procedure to study dependence and withdrawal resulting from A9-tetrahydrocannabinol (delta9-THC), a cannabinoid agonist that underlies the reinforcing, subjective, analgesic, and antiemetic effects of the marijuana plant. Marijuana is used by a large segment of the population and recent clinical studies have reported dependence on and withdrawal from delta9-THC and related cannabinoid agonists. Marijuana dependence could promote long-term marijuana use and polydrug abuse and could be a prominent factor underlying high comorbidity between marijuana use and certain mental disorders including panic, anxiety, depression, and psychosis. Very little is known about mechanisms underlying delta9-THC dependence and withdrawal because there are few pre-clinical assays that can be used to define these mechanisms. The procedures developed under this proposal are intended to satisfy this need for new pre-clinical assays that can be used to study delta9-THC dependence. Drug discrimination is uniquely sensitive to drug withdrawal and can measure aspects of withdrawal in non-human animals that cannot be directly observed. One strategy that has been applied successfully to the study of drug dependence and withdrawal is to train drug dependent animals to discriminate a competitive antagonist. This proposal will use standard two-lever operant procedures to train SR 141716A as a discriminative stimulus in a group of delta9-THC treated rhesus monkeys and in another group of untreated monkeys. Experiments will be designed to determine if the discriminative stimulus effects of SR 141716A in delta9-THC treated monkeys are related to delta9-THC withdrawal. Several criteria must be satisfied for this to be the case. First, the SR 141716A discriminative stimulus in A9-THC treated monkeys should be pharmacologically distinct from the SR 141716A discriminative stimulus in untreated monkeys, or SR 141716A should be demonstrated to maintain stimulus control in A9-THCtreated monkeys but not in untreated monkeys. Second, suspension of delta9-THC treatment should substitute for SR141716A in treated monkeys. Third, supplemental doses of delta9-THC should attenuate the SR 141716A discriminative stimulus or re-administration of delta9-THC during delta9-THC deprivation should reverse SR 141716A-appropriateresponding. The outcome of these experiments will determine whether this discrimination assay is related to delta9-THCwithdrawal and whether this assay can be used to define pharmacological mechanisms underlying delta9-THC dependence.
| Li, Jun-Xu; McMahon, Lance R; Gerak, Lisa R et al. (2008) Interactions between Delta(9)-tetrahydrocannabinol and mu opioid receptor agonists in rhesus monkeys: discrimination and antinociception. Psychopharmacology (Berl) 199:199-208 |
| McMahon, Lance R; Koek, Wouter (2007) Differences in the relative potency of SR 141716A and AM 251 as antagonists of various in vivo effects of cannabinoid agonists in C57BL/6J mice. Eur J Pharmacol 569:70-6 |
| McMahon, Lance R (2006) Discriminative stimulus effects of the cannabinoid CB1 antagonist SR 141716A in rhesus monkeys pretreated with Delta9-tetrahydrocannabinol. Psychopharmacology (Berl) 188:306-14 |
| McMahon, Lance R (2006) Characterization of cannabinoid agonists and apparent pA2 analysis of cannabinoid antagonists in rhesus monkeys discriminating Delta9-tetrahydrocannabinol. J Pharmacol Exp Ther 319:1211-8 |
