Hallucinogens, including the club drugs phencyclidine (PCP), ketamine, 3,4-methylenedioxy-N-methamphetamine (MDMA), and lysergic acid diethylamide (LSD), continue to be subject to widespread abuse by adolescents and young adults in this country. Data from the most recent National Survey on Drug Use and Health (SAMHSA, 2003) indicate that fully 45% of those using these drugs for the first time were under the age of 18. Among this class of drugs, the study of LSD and PCP offer perhaps a unique opportunity to elucidate and contribute to the understanding of psychosis as well as ameliorating the burdens of illicit and abusive drug use. Drug-induced stimulus control is a powerful tool for the study of behaviorally active drugs in intact animals that has identified clear distinctions in the mechanisms of action of non-competitive antagonists at the NMDA subtype of glutamate receptors, such as PCP, and serotonergic agents like LSD. However, it has also been observed that non-competitive antagonists of the NMDA receptor subtype potentiate the stimulus effects of both the phenethylamine hallucinogen (-)-2,5-dimethoxy-4-methylamphetamine (DOM) and LSD. Therefore, most recently, it has been hypothesized that glutamate release may be a final common pathway for the actions both of serotonergic and glutamatergic hallucinogens. This hypothesis draws support from behavioral studies using drugs that modify glutamate release in vivo that also have discriminative effects. However, a direct relationship between glutamate release and LSD-induced behavior is lacking. The objectives of the present proposal are to use a combination of behavioral and biochemical approaches to: [i] clarify the role of cortical glutamate release in the stimulus effects of LSD, and [ii] determine the effect of drugs that modulate LSD-induced behavior on extra cellular glutamate levels in the medial prefrontal cortex ? ? ?
