This is a request for an ADAMHA Research Scientist Development Award (RSDA) that will enable the applicant to engage in research, on essentially a full-time basis, for an extended period. By relieving the applicant from a particularly heavy teaching load which currently occupies approximately 40% of his time, the RSDA will allow the applicant to both focus on existing research activities and to develop competence in new areas for future research initiatives. Ongoing research (DA 07218) in the applicant's laboratory is focused on the mechanisms underlying dextrorotatory opioid interaction with the NMDA receptor. Dextrorphan is the major metabolite of dextromethorphan, a clinically used over-the-counter antitussive. Dextrorphan and related dextrorotatory morphinans and benzomorphans are similar to the dissociative anesthetics phencyclidine (PCP) and ketamine in that they act as selective noncompetitive antagonists of the NMDA receptor. Dextrorphan is unique in that it does not exhibit the striking use- dependence that is characteristic of the NMDA receptor blockade produced by PCP, ketamine and MK-801. The focus of ongoing research is to elucidate the molecular mechanisms which underlie the unique actions of dextrorphan. These studies utilize [H]dextrorphan as a probe for PCP receptors. Investigation of association and dissociation kinetics are being performed to delineate the mechanism of [H]dextrorphan binding to the PCP receptor in rat brain membranes. The distribution and pharmacological signature of [H]dextrorphan binding sites will be determined in brain slices using pharmacological signature of [H]dextrorphan binding sites will be determined in brain slices using quantitative receptor autoradiography. The potential for anatomically distinct forms of the labeled receptor is being assessed through investigation of biochemical and physiological regulation of the receptor. A further characterization of dextrorphan as a probe for the PCP receptor may provide useful insights into the mechanisms underlying and consequences of PCP and dextromethorphan abuse. An additional project (DA 05195, J.V. Aldrich, PI) in which the applicant is involved is focused on the characterization of synthetic dynorphin analogs as kappa opioid receptor antagonists. The goal of the applicant during the RSDA funding period is to continue to develop as a research scientist in the area of molecular pharmacology of abused drugs. Scientific growth will be enhanced through collaboration with a molecular biologist and an extended visit to the laboratory of a molecular pharmacologist. Specific training will be obtained in several areas of molecular biology.
