Hallucinogenic drugs act as agonists at 5HT2 and 5HT1C receptors. Given this common property, it is likely that one or both of these receptors plays a role in the actions of these drugs. The purpose of this grant is to understand how hallucinogenic drugs interact with brain 5HT2 and 5HT1C receptors and to explore the role of these receptors in the physiological and behavioral actions of hallucinogens. Previous studies of 5HT1C receptors utilized choroid plexus, a nonneuronal tissue in brain. Studies proposed in this grant will determine if hallucinogens activate 5HT1C receptors in nervous tissue - hippocampal slices - and if behaviorally active doses of hallucinogens activate 5HT1C and 5HT2 receptors in vivo. Protein kinase C translocation will provide an index of in vivo receptor activation. Blockade of this in vivo activity, in combination with protection experiments, will be used to establish antagonist treatments that selectively antagonize each receptor. These treatments will then be used to evaluate the role of each receptor in a behavioral effect of the hallucinogen 2,5-dimethyoxy-4-bromoamphetamine (DOB). Adaptive changes in DOB-induced behavior will be characterized and the role of receptor adaptation evaluated. Quantitative autoradiography will be used to monitor DOB-induced changes in 5HT2 receptors at discrete sites in the brain using both an agonist and antagonist radioligand. DOB-mediated phosphoinositide hydrolysis will also be examined in order to test the hypothesis that this functional measure will correlate with changes in agonist but not antagonist binding. A final series of experiments will attempt to address the relationship between activation of the phosphoinositide hydrolysis pathway, and a physiological event, membrane depolarization. For these experiments, the cloned 5HT2 receptor will be transfected into cell lines that have the requisite components for coupling to inhibition of K+ channels and to PI hydrolysis.
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