Dysfunction of serotonergic neurons that innervate the limbic system, including the hypothalamus, is implicated in depression. Since a single serotonergic neuron can innervate multiple limbic sites, it is possible that hypothalamic nuclei which control hormone secretion receive the same afferents that innervate other limbic areas. Several investigators have devised challenge tests that measure the effect of 5-HT agonists on plasma cortisol and prolactin in depressed patients. These tests may be useful to detect dysfunctional 5-HT neurons, and serve as a 'window into the limbic brain'. However, plasma cortisol and prolactin reflect activation of 5-HT1 receptor subtypes, whereas it is changes in 5-HT2 receptor subtypes that have been implicated in depression. We have preliminary evidence that brain serotonergic neurons stimulate vasopressin secretion by activation of 5-HT2 receptors. The objectives of this proposal are to establish which 5-HT neurons and receptor subtype(s) are involved in vasopressin secretion and to examine if the vasopressin response to 5-HT agonists can be used as a neuroendocrine marker of serotonergic function in depressed patients.
THE SPECIFIC AIMS OF THE PROPOSAL ARE: (1) To investigate the 5-HT receptor subtype(s) involved in vasopressin secretion by measuring the effect of selective 5-HT agonists, antagonists and releasers on plasma vasopressin levels. (2) To determine the serotonergic pathway(s) involved in vasopressin secretion. 5-HT releasing drugs release 5-HT only from intact neurons. Therefore, selective lesions of 5-HT pathways that will prevent the effect of 5-HT releasers will be used to indicate which 5-HT pathway(s) stimulate vasopressin secretion. Secondly, the 5-HT agonists and antagonists which were effective in Specific Aim I will be injected directly into different hypothalamic nuclei. This study will confirm the hypothalamic location and 5-HT receptor subtype which mediate vasopressin secretion. (3) To examine the effect of chronic injection of antidepressants on 5-HT2 receptors and the vasopressin response to 5-HT agonists. Since antidepressants produce a decrease in the density of 5-HT2 receptor subtypes, these studies may establish a correspondence between 5-HT 2 receptors and the vasopressin response to 5-HT agonists. Thus, changes in the vasopressin responsiveness may be useful in the evaluation of the antidepressant potential of new drugs.
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