The long-term goal of this Mentored Quantitative Research Career Award (K25) is to compliment the career preparation of the PI, an analytical chemist, with the training and research experience he needs to become a successful, independent researcher in drug abuse. This will be accomplished through a program of training and research in the pharmacology of drug abuse, focusing on the advanced areas of pharmacokinetics and behavioral pharmacology. In the final phase of this career development plan these diverse research areas will be integrated and used to conduct studies employing pharmacokinetic- pharmacodynamic (PK-PD) modeling. The mentor and co-mentor are both drug-abuse researchers with extensive research experience in these areas.
The aims of the research-training proposal are to investigate the pharmacology of dextromethorphan with regard to its actions as a drug of abuse. Dextromethorphan, a common component of cold and cough remedies, is an increasingly abused club drug (""""""""robo"""""""") among youth, often masquerading as more popular drugs such as MDMA (""""""""ecstasy"""""""") or gamma-hydroxybutyrate (""""""""GHB""""""""). The applicant will investigate the role of dextrorphan, the primary active metabolite of dextromethorphan, as the agent responsible for the phencyclidine-like actions of dextromethorphan. Because dextromethorphan is extensively metabolized to dextrorphan in the liver, first-pass effects play a significant role in its metabolism. To test the hypothesis that oral and intravenous administration of dextromethorphan will produce unique behavioral-time profiles, dose-response and time-course studies of spontaneous locomotor activity will be studied in rats. Concurrently, serum concentration-time profiles of dextromethorphan and metabolites will be determined. PK-PD modeling of response-time and concentration-time profiles will be used to determine in vivo pharmacodynamic parameters such as, intrinsic efficacy, estimated drug-receptor binding, and drug concentration at the effect site. This approach should provide evidence about whether dextromethorphan or dextrorphan, or both, are primarily responsible for the actions sought by abusers.
