The long term objectives of the work proposed herein are (a) elucidation of the mechanism of action of hallucinogenic agents (with particular emphasis on derivatives of phenalkylamines and indolealkylamines), (b) determination of the role of the neurotransmitter substance serotonin (5-HT) in such a mechanism, and (c) identification of structural characteristics required by a molecule in order for it to be hallucinogenic (achievement of this latter goal would allow the potential identification of those new drugs and abnormally produced endogenous substances which might possess hallucinogenic liability).
The specific aims of this present proposal are to identify those phenalkylamines (PAA) and indolealkylamines (IAA) that produce qualitatively similar behavioral effects and to then limit mechanistic studies to these agents. Using the discriminative stimulus paradigm, PAA and IAA derivatives will be administered to rats trained to discriminate DOM or amphetamine from saline. Generalization studies will provide information as to the """"""""DOM-likeness,"""""""" for example, of each of these agents. These data will then be compared with 5-HT receptor affinities (previously determined in these laboratories) and with 5-HT1 and 5-HT2 brain binding data in order to determine the role of these binding sites in the mechanism of action of the hallucinogens being studied (and in order to determine if fundus 5-HT receptors are similar to either of these binding sites). Finally, because it appears that hallucinogenic PPAs and IAAs might be acting in vivo as 5-HT agonists, several novel serotonergic agents, including latent 5-HT analogs, will be synthesized and evaluated to challenge this hypothesis. The novelty of our approach is (a) that an in vivo """"""""drug detection"""""""" paradigm is being used (to obtain qualitative as well as quantitative data) in order to assure that each of the agents under study is producing a common effect, and (b) that medicinal chemical principles are being employed to design and synthesize agents that will aid in determining the role of 5-HT1 vs. 5-HT2 binding as it relates to hallucinogenic agents. Thus, this study should afford a better understanding of certain classes of drugs of abuse and will also shed light on the functional role of a major neurotransmitter.
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