PAS-06-Q66 identifies a need for novel directions in the development of medications against drug addictions. To answer this need, we plan to synthesize and pharmacologically evaluate novel cannabinergic-1 (CB1) partial agonists and antagonists for the management of methamphetamine addiction. Methamphetamine addiction has become a world-wide epidemic, and is recognized as the most serious drug abuse problem in this country today. Addiction to methamphetamine, like other abused drugs, can be characterized as a recurring disease involving abuse, addiction, transition to drug-free status, and relapse. Different medications may be effective at different points in the cycle. We propose that CB1 partial agonists, through actions that overlap those of methamphetamine, may-assist in the transition to drug-free status and that CB1 antagonists, by dampening or masking the effects of stimuli that trigger drug-seeking behavior, may help prevent relapse. Our approach is based upon an emerging literature and our own laboratory observations indicating that a) CB1 agonists and methamphetamine have convergent neurochemical and behavioral actions;and b) CB1 antagonists may lessen the impact of drugs or conditions that instigate drug-seeking behavior. In our proposed research, we will use chemical templates that we and others have developed for cannabinergic ligands to design and construct novel lead compounds. Our goal is to generate analogs that vary in duration of action and pharmacological efficacy and will include both partial agonists and antagonists with neutral or inverse agonist activity. Our strategy will be to conduct side-by-side comparisons with the partial agonist A9THC and the inverse agonist SR141716A whenever possible. Novel CB1 ligands that meet efficacy criteria in biochemical studies will then be studied in rats to confirm their biological activity in hypothermia and drug discrimination studies. Next, we will use drug discrimination procedures to evaluate overlap in the 'subjective'effects of methamphetamine and novel CB1 partial agonists and, also, the ability of B1 antagonists to mute methamphetamine's stimulus effects. Finally, the most promising CB1 ligands will be further evaluated in our i.v. self-administration food/drug 'choice'procedures. We expect CB1 partial agonists to reduce methamphetamine's reinforcing strength, i.e., the proportion of behavior that it commands. We also expect CB1 antagonists to dampen the ability of low doses of noncontingently delivered methamphetamine to engender drug-seeking behavior, i.e., re-allocation of behavior toward i.v. injections and away from non-drug reinforcement. Overall, our proposed studies will permit highly significant progress toward the identification of cannabinergic candidates for drug development and, eventually, novel cannabinergic medications to combat different phases of methamphetamine addiction. This will be a significant contribution to the improvement of public health.
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