Rats and genetically altered mice will be used to determine the involvement of serotonergic and other systems in the behavioral effects of hallucinogens, such as lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-methylamphetamine (DOM), or phencyclidine (PCP); and serotonin (5HT) releasers, such as 3,4- methylenedioxymethamphetamine (MDMA) and alpha-ethyltryptamine (AET). Behavioral effects will be measured using acoustic and tactile startle paradigms to assess habituation and sensorimotor gating (prepulse inhibition-PPI) functions and computerized monitoring of patterns of locomotor and investigatory behavior, using a Behavioral Pattern Monitor in rats and a Video Tracker in mice.
Aim 1 will identify the mechanisms and sites of action mediating the locomotor-activating effects of indirect serotonin agonists, such as MDMA or AET, and direct agonists, such as RU24969, by testing the hypothesis that postsynaptic 5HTIB receptors mediate these effects of serotonin-releasing agents.
Aim 2 will test the hypotheses that indirect serotonin agonists: [1] disrupt PPI in rats by acting indirectly via 5HTIB and/or 5HT2A receptors; and [2] impair startle habituation in rats by acting indirectly on 5HT2A receptors; and [3] have effects on PPI in mice that depend upon a balance between the opposing influences of indirect activation of postsynaptic 5HTIA receptors versus 5HTIB and/or 5HT2A receptors. Knockouts of 5HTIA and 5HTlB receptors will be studied.
Aim 3 will clarify the mechanisms and sites of action by which serotonergic hallucinogens, such as LSD and DOM, and glutamatergic hallucinogens, such as PCP, disrupt startle habituation and PPI.
Aim 4 will identify the mechanisms and sites of action mediating the effects of hallucinogens on exploratory behavior, testing the hypothesis that both 5HTlA and 5HT2 receptors contribute to the effects of indoleamine, but not phenalkylamine, hallucinogens. The brain regions involved in a proposed functional interaction between 5HTlA and 5HT2 receptors will be identified, as will the sites of action at which 5HT2 receptors modulate the effects of PCP on locomotor activity. These studies should further our basic understanding of the behavioral functions of serotonergic systems and the mechanisms of action of drugs of abuse such as hallucinogens and serotonin releasers.
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