5-HT2A receptors stimulate ACTH, corticosterone, oxytocin, renin, and prolactin release and activate hypothalamic CRF and oxytocin-expressing cells

The 5-HT2A/2C agonist (+/-)-1-( 2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI) stimulates hypothalamic neurons to increase the secretion of seve ral hormones. This study addressed two questions: 1) are the neuroendocrine effects of DOI mediated via activation of 5-HT2A receptors; and 2) which n eurons are activated by 5-HT2A receptors. The 5-HT2A antagonist (+)-alpha-( 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 w ere challenged with DOI (2.5 mg/ kg, i. p.). MDL 100,907 produced a dose- d ependent inhibition (ED50 congruent to 0.001 mg/ kg) of the effect of DOI o n plasma levels of ACTH, corticosterone, oxytocin, prolactin, and renin wit hout 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 it s 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 vasop ressin- containing neurons in the hypothalamic paraventricular nucleus or C RF 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 includi ng the hypothalamus, amygdala (central and corticomedial), bed nucleus of t he stria terminalis, and prefrontal cortical regions. The combined neuroana tomical and pharmacological observations suggest that the neuroendocrine re sponses to DOI are mediated by activation of neurons in the hypothalamic pa raventricular nucleus and associated circuitry. Furthermore, selective acti vation of 5-HT2A receptors mediates the hormonal and Fos- inducing effects of DOI.