Evidence That 5-HT_2AReceptors in the Hypothalamic Paraventricular Nucleus Mediate Neuroendocrine Responses to (−)DOI

Abstract

The present study determined whether the serotonin2A (5-HT2A) receptors in the hypothalamic paraventricular nucleus mediate the neuroendocrine responses to a peripheral injection of the 5-HT2A/2C receptor agonist (-)DOI [(-)1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane]. The 5-HT2A receptor antagonist MDL100,907 ((+/-)-alpha(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol), the 5-HT2C 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-HT2A receptor antagonist nor the 5-HT2C 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-HT2A receptors in the hypothalamic paraventricular nucleus, 5-HT2A 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-HT2A 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-HT2A receptors in the hypothalamic paraventricular nucleus.

Cocaine-mediated supersensitivity of 5-HT2A receptors in hypothalamic paraventricular nucleus is a withdrawal-induced phenomenon

“…In the present study, the (â)DOI-evoked release of corticosterone and prolactin was greater in rats undergoing cocaine withdrawal, a result that is consistent with reports in the literature (Baumann et al, 1993;Baumann and Rothman, 1998;Levy et al, 1992). We have previously reported that the neuroendocrine effects of (â)DOI, are mediated exclusively by activation of 5-HT 2A receptors (but not 5-HT 2C receptors) in the PVN (Zhang et al, 2002). Consequently, the potentiated responses to (â)DOI of two different hormones (prolactin and corticosterone) that are mediated by distinct signaling pathways suggests supersensitivity mediated at the level of 5-HT 2A receptor signal transduction.…”

A Genetically Defined Morphologically and Functionally Unique Subset of 5-HT Neurons in the Mouse Raphe Nuclei

“…For instance, in the BLA, where 5-HT boutons form synapses, 5-HT2A, 5-HT2C, and 5-HT3 receptors are the main receptors (Wright et al, 1995;McDonald and Mascagni, 2007;Muller et al, 2007). 5-HT2A and 5-HT2C receptors are also strongly expressed in the hypothalamic paraventricular nucleus and intralaminar thalamic nuclei, with preserved innervation in the Pet1 knock-out (Zhang et al, 2002;Heisler et al, 2007).…”

Sustained treatment with a 5-HT2A receptor agonist causes functional desensitization and reductions in agonist-labeled 5-HT2A receptors despite increases in receptor protein levels in rats

“…The neuroendocrine response to serotonergic activation has been used as a diagnostic tool to examine the functioning of serotonergic neurons in the brains of patients suffering from mood disorders (Lerer, et al, 1999). The presence of 5-HT 2A receptors in the hypothalamic PVN is supported by autoradiographic (Appel, et al, 1990), in situ hybridization (Gundlah, et al, 1999;Wright, et al, 1995) and immunohistochemical labeling studies (Zhang, et al, 2002). 5-HT 2A receptors in the hypothalamic PVN mediate the neuroendocrine responses to an acute peripheral injection of the selective 5-HT 2A/C receptor agonist, DOI.…”

“…5-HT 2A receptors in the hypothalamic PVN mediate the neuroendocrine responses to an acute peripheral injection of the selective 5-HT 2A/C receptor agonist, DOI. This was demonstrated using both intra-PVN and peripheral injections of the selective 5-HT 2A receptor antagonist MDL 100,907 which dose-dependently inhibited the effect of DOI (1 mg/kg, s.c.) on hormone secretion (HemrickLuecke and Evans, 2002; Van de Kar, et al, 2001;Zhang et al, 2002). Thus, plasma hormone levels can be used as an index of the function of 5-HT 2A receptor signaling in the hypothalamic PVN.…”