Behavioral and Pharmacological Analysis of Drugs of Abuse

6. Project Summary/Abstract Hallucinogens of all types are subject to widespread abuse especially by adolescents and young adults in this country. Perhaps equally important is the possibility that these drugs may offer clues to the etiology of the most serious forms of mental illness. The long-term objectives of the present proposal are to characterize hallucinogens behaviorally and pharmacologically with the ultimate goal of establishing their mechanisms of action. Although they are united by a common term, hallucinogen, these drugs represent distinct pharmacological entities. Lysergic acid diethylamide [LSD] is chemically and pharmacologically quite different from the simpler indoleamines represented by DMT and psilocybin. Indeed, in terms of a presumed receptor mechanism of hallucinogenic action, LSD more closely resembles a phenethylamine such as mescaline. Nonetheless, all of these drugs are joined by prominent activity via serotonergic [5- hydroxytryptaminergic] mechanisms. Until recently, the same could not be said for phencyclidine [PCP, Angel Dust]. However, a unifying serotonergic-glutamatergic mechanism is beginning to emerge with the hypothesis that glutamate release may represent a final common pathway for hallucinogens. Nonetheless, to say that all of these drugs are somehow serotonergic in nature obscures the fact that 14 distinct serotonergic receptors are known, each with a distinct neuroanatomic distribution and array of functions. The decision to focus in the present proposal on, 5-HT2c, 5-HT7, 5-HT2~a,n d 5-HTqAr eceptors is based upon suggestive pharmacological and behavioral evidence, which links these receptors to hallucinogenesis. The primary behavioral index will continue to be the stimulus effects of hallucinogens in rodents, effects widely believed to have significant subjective correlates in humans. In addition, hallucinogens will be characterized using in vivo microdialysis to correlate glutamate release with behavioral activity. It is expected that integration of the resulting data will provide new understanding of the mode of action of hallucinogens, especially those subject to abuse. In addition, these studies may contribute to our understanding of the most serious forms of mental illness including anxiety, depression, and psychosis. Finally, the role of the internet in expanding interest in these and other club drugs such as MDMA [Ecstasy] especially among youthful segments of society is inestimable but will almost certainly lead to increased illicit use. This likelihood coupled with continued interest in the therapeutic use of agents such as psilocybin makes a detailed pharmacological assessment of these drugs of utmost importance.