This project focuses on the pharmacology of brain serotonin (5-HT) neurons after chronic exposure to 5-HT uptake blockers. Impaired function of 5-HT1A receptors has been associated with neurological and psychiatric disorders. Chronic exposure to 5-HT uptake blockers reduces 5-HT1A receptor function of serotonergic cells in the midbrain. However, little information is currently available regarding the effect of 5-HT uptake blockers on hypothalamic post-synaptic 5-HT1A receptors. Moreover, no studies have investigated such fundamental issues as the time- course, dose-response relationship or duration of the effects of 5-HT uptake blockers on 5- HT1A receptor function. The applicant has recently found that the 5-HT uptake blocker fluoxetine (10 mg/kg/day, 21 days) reduces 5-HT1A receptor-mediated plasma ACTH and oxytocin responses in a time-dependent manner. A single injection of fluoxetine had no effect. The hypothesis is advanced that chronic exposure to 5-HT uptake blockers causes adaptational changes in serotonergic neurotransmission, resulting in reduced 5-HT1A receptor function in the hypothalamus. The proposed studies will characterize the changes in hypothalamic post-synaptic 5- HT1A receptors induced by chronic exposure to 5-HT uptake blockers. Biochemical approaches will focus on changes in 5-HT1A receptor density and their signal transduction mechanisms (coupling to G-proteins). In addition, the responsiveness of hypothalamic 5-HT1A receptors will be determined from the neuroendocrine responses to specific 5- HT1A agonists.
Specific Aim 1 will investigate the time-course of effects of 5-HT uptake blockers on hypothalamic 5-HT1A receptors, their signal transduction mechanisms, and endocrine responses to 5-HT1A agonists.
Specific Aim 2 will determine the dose-response effects of chronic exposure to 5-HT uptake blockers on 5-HT1A receptors, their signal transduction mechanisms, and hormone responses mediated by 5-HT1A receptors. So far, studies have used doses that are 10 fold higher than clinically relevant doses. This study will determine the minimal dose of fluoxetine that will reduce 5-HT1A receptor function. The final Specific Aim will determine the duration of altered 5- HT1A receptor function after withdrawal from 5-HT uptake blockers. A comparison of endocrine changes with biochemical indices of 5-HT1A receptor function may provide a model of withdrawal from 5-HT uptake blockers.
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