The abuse of phencyclidine (PCP) and ketamine remain important public health problems, yet relatively less basic scientific information is available on this class of drugs than some other, more widely studied, abused drugs. One goal of our research is to continue to advance our understanding of the pharmacology of this class of PCP-like drugs. In previous years of this project, we have shown that PCP-like drugs functioned as antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor to produce behavioral effects in animals that are relevant to their abuse potential. NMDA antagonists are possible treatments for drug tolerance and dependence. Other important indications for NMDA antagonists include use for treatment of epilepsy, head injury and stroke, anxiety and panic disorders and pain. Thus, another significant goal of our work is to provide scientific information that can lead to the development of medications that have diminished capacity for PCP-like psychological effects and abuse liability. Our strategy for doing this is to compare the behavioral pharmacology of NMDA antagonists that act at various sites on the NMDA receptor complex, including PCP-site channel blockers which vary in affinity and other important characteristics, competitive antagonists, glycine-site antagonists, polyamine-site antagonists as well as NMDA receptor subtype selective agents using well validated animal testing procedures in rats and rhesus monkeys. These types of drugs will be compared using 1) Drug discrimination in rats and rhesus monkeys using NMDA antagonists as training drugs, 2) Drug vs. drug discrimination in rats and rhesus monkeys to further differentiate similar drug effects identified in drug vs. no-drug discrimination, 3) Intravenous drug self-administration in rhesus monkeys, 4) Drug discrimination in rats using novel GABAergic drugs, 5) Tests for anti-anxiety effects using a multiple drug discrimination-punished responding schedule in rats, and 6) Tests for effects on the efficacy of intravenous cocaine reinforcement in rhesus monkeys using a procedure which will also allow assessment of effects on conditioned reinforcement which might be involved in cocaine craving. This latter study is part of a planned continued collaboration with scientists at the Pavlov Medical University in St. Petersburg supported under a Fogerty Center grant tied to this project. Finally, the hypothesis that subtypes of NMDA receptors comprised of NR2A subunits are important for mediating PCP discrimination will be tested using antisense procedures directed to knocking down the expression of this and other subunits.
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