5-HT_2AReceptors Stimulate ACTH, Corticosterone, Oxytocin, Renin, and Prolactin Release and Activate Hypothalamic CRF and Oxytocin-Expressing Cells

TLDR

The 5‑HT2A/2C agonist DOI activates hypothalamic neurons, increasing secretion of multiple hormones. The study aimed to determine whether DOI’s neuroendocrine effects are mediated by 5‑HT2A receptors and to identify the specific neurons activated. Rats received the 5‑HT2A antagonist MDL 100,907 at 0.001–0.1 mg/kg before DOI (2.5 mg/kg) to assess hormone levels and Fos expression in hypothalamic nuclei. MDL 100,907 dose‑dependently blocked DOI‑induced rises in ACTH, corticosterone, oxytocin, prolactin, and renin, and prevented DOI‑induced Fos in CRF and oxytocin neurons, indicating that 5‑HT2A receptor activation in the PVN drives these neuroendocrine responses.

Abstract

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 (+)-α-(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 (ED 50 ≅ 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.