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

Abstract

The 5-HT 2A/2C agonist (Ϯ)-1-(2,5-dimethoxy-4-iodophenyl)-2aminopropane 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 (ϩ)-␣-(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 Х 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.

Imaging Brain Phospholipase A2 Activation in Awake Rats in Response to the 5-HT2A/2C Agonist (±)2,5-Dimethoxy-4-Iodophenyl-2-Aminopropane (DOI)

“…These increments are consistent with the reported marked behavioral (5-HT 2 syndrome) and neuroendocrine responses provoked by this dose (Johnson et al, 1998;Pranzatelli, 1990;Van de Kar et al, 2001;Wettstein et al, 1999). The increments in k* could be completely blocked by chronic pretreatment with mianserin, a 5-HT 2 receptor agonist that has been reported to block the 5-HT 2 syndrome and the hyperthermia produced by DOI (Berendsen and Broekkamp, 1991;Mazzola-Pomietto et al, 1997).…”

“…Additionally, 2.5 mg/kg i.p. DOI in rats markedly stimulates the release of corticotropin (ACTH), corticosterone, oxytocin, renin, and prolactin, and activates hypothalamic corticotropin-releasing factor and oxytocin-expressing neurons (Van de Kar et al, 2001). DOI also induces hyperthermia in rats (MazzolaPomietto et al, 1997).…”

Opposing actions of 5HT1A and 5HT2-like serotonin receptors on modulations of the electric signal waveform in the electric fish Brachyhypopomus pinnicaudatus

“…While each of these agonists has high affinity for 5HT 2 receptors and differentiates well against other 5-HT receptor families, they do not exhibit reliable selectivity between the three receptor subtypes in this family: 5HT 2A , 2B , and 2C Hoyer et al, 2002;Jerman et al, 2001;Ramage, 2005;Van de Kar et al, 2001). Modulations of the EOD in response to one or more of these ligands would therefore support involvement of at least one 5HT 2 receptor type; however such a response would not exclude involvement of the other subtypes in regulating the EOD.…”

Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions

“…56 5-HT2A and 2C receptors are involved in the release of prolactin, and agonists of these receptors increase the secretion of this hormone. 57,58 The antagonistic effect exerted by risperidone on these receptors will inhibit prolactin secretion, therefore counteracting the increase induced by risperidone binding to D2 receptors. The presence of a HTR2A-1438G allele leads to a lower density of these receptors, 37,38 resulting in higher prolactin secretion and increased levels of this hormone in patients homozygous for this allele, and also to a diminished therapy response (as described above).…”