To clarify the involvement of central serotonergic systems in the behavioral effects of hallucinogens in rats, studies of hallucinogen-induced decreases in startle habituation and increases in behavioral measures of neophobia will be extended to include 3,4-methylenedioxy amphetamine (MDA), 3,4-methylenedioxy-N- methylamphetamine (MDMA, """"""""Ecstasy""""""""), N-ethyl-3,4-methylenedioxy- amphetamine (MDEA, Eve), and their stereoisomers. The behavioral effects of the hallucinogens and related drugs will be thoroughly characterized using measures of acoustic and tactile startle responses and a computerized Behavioral Pattern Monitor that provides detailed information regarding the amount and qualitative patterning of spontaneous activity and investigatory responses to specifiable environmental stimuli. The ability of serotonin releasing agents, such as p-chloroamphetamine (PCA) and fenfluramine, to mimic the effects of the hallucinogens and the ability of serotonin-2 antagonists to block them will be determined. The effects of selective neurotoxic lesions of serotonin in localized protection sites in brain will be similarly characterized. Lesion effectiveness and specificity will be assessed with histofluorescence microscopy and regional monoamine assays using liquid chromatography with electrochemical detection. The hypothesis that specific serotonergic terminal regions are responsible for the acute effects of MDA, MDMA, MDEA, and PCA on startle habituation and the potentiation of neophobia will be tested by examining the effects of these drugs in lesioned animals. Experiments will also test the possibility that neurotoxic lesions or acute administrations of the hallucinogenic amphetamine derivatives lead to long-lasting changes in the behavioral responsiveness of animals to serotonergic agonists. This work should further our understanding of the basic neural mechanisms mediating the behavioral effects of these drugs of abuse. facilitate the development of antagonists for their effects, and begin to clarify the long-term functional consequences of their use.
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