The overall goal- of our work is elucidation of the mechanisms of action of classical hallucinogens and structurally related phenylisopropylamines (PIAs) and indolealkylamines (IAAs). Due to a multiplicity of action for certain agents, however, such studies require that these agents first be appropriately categorized. For example, PIA drugs of abuse can be divided into three broad categories: hallucinogens (e.g. DOM, DOB), central stimulants (e.g. amphetamine or AMPH), and designer drugs. We have demonstrated, using the drug discrimination paradigm, that certain designer drugs produce DOM-like effects, some produce AMPH-like effects, some (e.g. MDA) produce both effects, and yet others (e.g. PMMA) produce neither. We have proposed the 5-HT2 hypothesis to account for the actions of PIA and IAA hallucinogens. AMPH-like central stimulants likely act via a catecholaminergic mechanism. The mechanism of action of non-DOM- like/non-AMPH-like designer drugs is unknown. Although the 5-HT2 hypothesis suggests that classical hallucinogens are 5-HT2 agonists, this has never been adequately demonstrated; it is proposed to determine the efficacy of classical hallucinogens by examining their effect on PI metabolism. Due to the discovery of a novel population of 5-HT2 receptors, 5-HT2B receptors, we propose to determine their role, if any, in the action of classical hallucinogens by conducting radioligand binding studies. PMMA is a new PIA designer drug that lacks DOM-like and AMPH-like properties; we propose to investigate this agent using drug discrimination techniques with rats as subjects. Also, because evidence suggests that the different effects of PIA drugs of abuse may be related to different side-chain conformations, we propose to synthesize and evaluate a series of novel conformationally-restricted agents specifically designed to test this hypothesis. Finally, although IAAs of abuse are typically considered only as being hallucinogenic, we provide evidence that they, like the PIAs, may also be divided into several categories. For example, the new designer drug alpha-ET produces central stimulant and DOM-like effects, as well as non-DOM-like and non- AMPH-like effects. We propose to investigate this novel agent in drug discrimination studies. Thus, in summary, we intend to further validate the 5-HT2 hypothesis of hallucinogenic drug action while, at the same time, to investigate the actions of several new and interesting structurally-related PIA and IAA designer drugs.
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