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The Journal of Neuroscience, May 15, 2001, 21(10):3572-3579

5-HT_2A Receptors Stimulate ACTH, Corticosterone, Oxytocin, Renin, and Prolactin Release and Activate Hypothalamic CRF and Oxytocin-Expressing Cells

Louis D. Van de Kar^{1, 2}, Adil Javed^{1, 3}, Yahong Zhang^{1, 2}, Florence Serres^{1, 2}, Daní K. Raap^{1, 2}, and Thackery S. Gray^{1, 3}

¹ The Center for Serotonin Disorders Research and the Departments of ² Pharmacology and ³ Cell Biology, Neuroscience and Anatomy, Loyola University of Chicago, Stritch School of Medicine, Maywood, Illinois 60153

The 5-HT_2A/2C agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI) stimulates hypothalamic neurons to increase the secretion of several hormones. This study addressed two questions: 1) are the neuroendocrine effects of DOI mediated via activation of 5-HT_2A receptors; and 2) which neurons are activated by 5-HT_2A receptors. The 5-HT_2A antagonist (+)--(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (MDL 100,907; 0.001, 0.01, or 0.1 mg/kg, s.c.) was administered before rats were challenged with DOI (2.5 mg/kg, i.p.). MDL 100,907 produced a dose-dependent inhibition (ED₅₀  0.001 mg/kg) of the effect of DOI on plasma levels of ACTH, corticosterone, oxytocin, prolactin, and renin without altering basal hormone levels. Complete blockade of the effect of DOI was achieved for all hormones at MDL 100,907 doses of 0.01-0.1 mg/kg. In a parallel experiment, DOI was injected 2 hr before killing to determine its effects on the expression of Fos, the product of the immediate early gene c-fos. DOI induced an increase in Fos immunoreactivity in corticotropin-releasing factor (CRF) and in oxytocin-expressing neurons but not in vasopressin-containing neurons in the hypothalamic paraventricular nucleus or CRF cells in the amygdala. Pretreatment with MDL 100,907 (0.1 mg/kg, s.c.) blocked the DOI-induced increase in Fos expression in all regions including the hypothalamus, amygdala (central and corticomedial), bed nucleus of the stria terminalis, and prefrontal cortical regions. The combined neuroanatomical and pharmacological observations suggest that the neuroendocrine responses to DOI are mediated by activation of neurons in the hypothalamic paraventricular nucleus and associated circuitry. Furthermore, selective activation of 5-HT_2A receptors mediates the hormonal and Fos-inducing effects of DOI.

Key words: serotonin; ACTH; oxytocin; MDL 100,907; c-fos; Fos; prolactin; renin; corticosterone

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21103572-08$05.00/0

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