This project outlines studies designed to lead to the development of chemical molecules which have the ability specifically to release endogenous serotonin from brain serotonin neurons. The target compounds will not produce long-term deficits in central serotonin markers, as is typical of other such agents such as parachloroamphetamine or fenfluramine. This project has immediate application, as the drugs which are developed will be useful as pharmacological tools to study the role of brain serotonin systems in a variety of behaviors. These molecules should have significance to the study of serotonin systems comparable to that of amphetamine for studying dopaminergic systems. The long range significance of this work will lie in a better understanding of the role serotonin plays in emotion and behavior. In addition, serotonin-releasing agents may prove to have utility in the treatment of conditions such as depression and anxiety disorders which are now effectively treated with serotonin uptake inhibitors. This proposal targets several types of chemical structures, including para-alkylthioamphetamine derivatives, 5- alkylthio-2-aminoindans, ring-methylated 3,4-methylenedioxyamphetamine derivatives, and 5-trifluoromethyl-2-aminoindan and its N-ethyl derivative, the latter which are rigid analogues of fenfluramine and norfenfluramine. Following synthesis, new compounds will be screened in a battery of assays, initially including ability to inhibit monoamine accumulation into rat brain synaptosomes and to induce the overflow of transmitter from prelabeled superfused synaptosomes. In addition, tests for cross-substitution in the two-lever drug discrimination paradigm will assess whether the compounds are more similar in vivo to serotonin releasing agents, hallucinogens, or psychostimulants. Acute and long-term effects on brain monoamines will be assessed using HPLC-EC, with a particular emphasis on acute and long-term effects on serotonin neuron markers as an indication of potential serotonergic neurotoxicity of new compounds. This will provide data to continue our testing of the hypothesis that substituted amphetamines must release both serotonin and dopamine to induce long-term serotonergic deficits. Compounds will be evaluated for reinforcing effects using conditioned place preference, to assess the validity of the hypothesis that only compounds with dopaminergic activity will induce place preference. In vivo microdialysis will be used to measure changes in extracellular dopamine in the rat nucleus accumbens to test further the hypothesis that increased accumbens dopamine levels are correlated with ability to induce place preference.
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