Studies in rats are proposed to further clarify the involvement of central serotonergic systems in the behavioral effects of acute administrations of both traditional hallucinogens, such as lysergic acid diethylamide (LSD) and 2,5-dimethoxy-4-methylamphetamine (DOM), as well as serotonin releasers such as 3,4-methylenedioxy-N-methylamphetamine (MDMA, """"""""Ecstasy""""""""), N-methyl-l-(l,3-benzodioxol-5-yl)-2-butanamine (MBDB), and N- ethyl-3,4-methylenedioxy-amphetamine (MDEA, """"""""Eve""""""""). The behavioral effects of the hallucinogens, serotonin releasers, 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 patterning of spontaneous activity and investigatory responses to specifiable environmental stimuli.
Five specific aims are proposed.
Aim l will identify the mechanisms and sites of action subserving the locomotor activating effects of indirect serotonin agonists such as MDMA or MBDB, testing the hypothesis that postsynaptic 5HTIB receptors within the basal ganglia mediate these effects.
The second aim will test the hypothesis that indirect serotonin agonists, including MDMA and MBDB, impair the habituation of startle by acting via the release of presynaptic serotonin, which acts in turn upon postsynaptic 5HT1C/2 receptors.
The third aim i s to characterize the mechanisms underlying the disruptive effects of MDMA-like serotonin releasers on prepulse inhibition of startle, an operational measure of sensori-motor gating. The hypothesis to be tested is that these effects are attributable to the release of presynaptic serotonin. Antagonists will be used to identify the serotonin receptor subtype(s) responsible for these effects. Experiments will also test the hypothesis that the disruption of startle prepulse inhibition produced by LSD is attributable to its actions as a partial agonist at 5HTlA receptors.
Aim 4 will clarify the mechanisms by which traditional hallucinogens produce their characteristic effects on exploratory behavior, including the potentiation of both neophobia and agoraphobia. Experiments will use antagonists and combinations of agonists to test the hypotheses that a functional interaction exists between the actions of 5HTlA and 5HT1C/2 receptors and that 5HT1A receptors contribute to the effects of LSD.
Aim 5 will use receptor antagonists and cross-tolerance regimens to test the hypothesis that 5HT1A receptors contribute to the effects of LSD on startle habituation. The work should further our understanding of the' basic neural mechanisms mediating the behavioral effects of these drugs of abuse and facilitate the_development of antagonists for their effects.
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