Evidence That 5-HT2AReceptors in the Hypothalamic Paraventricular Nucleus Mediate Neuroendocrine Responses to (−)DOI

The present study determined whether the serotonin(2A) (5-HT(2A)) receptors in the hypothalamic paraventricular nucleus mediate the neuroendocrine responses to a peripheral injection of the 5-HT(2A/2C)receptor agonist (−)DOI [(−)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane]. The 5-HT(2A) receptor antagonist MDL100,907 ((±)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol), the 5-HT(2C) receptor antagonist SB-242084 (6-chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-indoline), or vehicle were microinjected bilaterally through a chronically implanted double-barreled cannula into the hypothalamic paraventricular nucleus 15 min before a peripheral injection of (−)DOI in conscious rats. (−)DOI significantly elevated plasma levels of oxytocin, prolactin, ACTH, corticosterone, and renin. Neither the 5-HT(2A) receptor antagonist nor the 5-HT(2C)receptor antagonist, injected alone, altered the basal levels of these hormones. MDL100,907 (0.748, 7.48, and 18.7 nmol) dose dependently inhibited the (−)DOI-induced increase in all of the hormones except corticosterone. In contrast, SB-242084 (10 nmol) did not inhibit (−)DOI-increased hormone levels. To confirm the presence of 5-HT(2A) receptors in the hypothalamic paraventricular nucleus, 5-HT(2A) receptors were mapped using immunohistochemistry. Densely labeled magnocellular neurons were observed throughout the anterior and posterior magnocellular subdivisions of the hypothalamic paraventricular nucleus. Moderately to densely labeled cells were also observed in parvicellular regions. Thus, it is likely that 5-HT(2A) receptors are present on neuroendocrine cells in the hypothalamic paraventricular nucleus. These data provide the first direct evidence that neuroendocrine responses to a peripheral injection of (−)DOI are predominantly mediated by activation of 5-HT(2A) receptors in the hypothalamic paraventricular nucleus.