The long-term goal of this research is to identify the pharmacodynamic and pharmacokinetic mechanisms of dextromethorphan abuse. Dextromethorphan is a common and effective antitussive component of many over-the-counter medications. There is also recent interest in dextromethorphan as a potential treatment for epilepsy, various neuromuscular conditions, neuropathic pain, stroke, and for the treatment of opioid addiction. However, it is also an abused drug and there are indications that the abuse of dextromethorphan is increasing. Despite the interest in dextromethorphan as a therapeutic agent, medical science is hindered by a lack of knowledge concerning the mechanisms of action that lead to its abuse. In the large doses that are typically abused, the psychological and physiological effects resemble those of phencyclidine (PCP). To add to the problem, dextromethorphan is rapidly metabolized by most people, but 5-10% of the U.S. population are deficient in the liver enzyme that catalyzes its metabolism (CYP2D6). Poor metabolizers produce a different pattern of metabolites and may be more sensitive to the adverse effects of dextromethorphan and other drugs that share this metabolic pathway. Our hypothesis is that dextromethorphan produces the effects for which it is abused, directly or in combination with its metabolites, by mechanisms it shares with PCP and other non-competitive antagonists of the NMDA-receptor complex. We propose to investigate this hypothesis with integrated studies of dextromethorphan pharmacokinetics and discriminative stimulus effects in two strains of rats: the Sprague-Dawley rat, which metabolizes dextromethorphan like most humans, and the dark Agouti rat, which is a model of the human poor-metabolizer phenotype. Drug discrimination techniques have proven useful for classifying drugs according to their molecular mechanisms of action and are thought to reflect a subset of the subjective effects of drugs in humans which play a major role in the initiation and maintenance of drug taking behavior. Combining studies of metabolism with studies of behavioral pharmacology is a unique and powerful approach for correlating the pharmacokinetic and pharmacodynamic effects of dextromethorphan. Ultimately, these integrated studies should add to our understanding of dextromethorphan's pharmacology with regard to its actions as a drug of abuse.

R01DA010358

1998-04-15

2002-03-31