5-Hydroxytryptamine 1A Receptors in the Paraventricular Nucleus of the Hypothalamus Mediate Oxytocin and Adrenocorticotropin Hormone Release and Some Behavioral Components of the Serotonin Syndrome

Abstract

Neuroendocrine responses to administration of serotonin releasing agents or 5-hydroxytryptamine (5-HT) 1A receptor agonists have been used as an index of serotonin receptor function in patients with depression and other mood disorders. However, the receptor population that mediates these responses has not been clearly identified. We tested the hypothesis that 5-HT1A receptors in the paraventricular nucleus of the hypothalamus (PVN) mediate the release of adrenocorticotropin hormone (ACTH) and oxytocin after administration of a selective 5-HT1A agonist in conscious rats. Low-dose infusion (1 nmol/ 100 nl/side) of the selective 5-HT1A antagonist, WAY100635 (WAY; [O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl) ethyl)-N-(2-pyridinyl)cyclohexanecarboxamidetrihydrochloride), into the PVN blocked the rise in ACTH and oxytocin stimulated by low-dose (30 nmol/kg) i.v. administration of the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 274 Ϯ 53 versus 70 Ϯ 20 pg/ml, P Ͻ 0.01 for ACTH and 10.7 Ϯ 3.4 versus 4.6 Ϯ 0.7 pg/ml, P Ͻ 0.05 for oxytocin after saline or WAY pretreatment, respectively). WAY did not influence the bradycardic effect of 8-OH-DPAT (Ϫ56 Ϯ 7 versus Ϫ54 Ϯ 6 beats per minute after saline or WAY). 8-OH-DPAT treatment also elicited locomotor activation followed by hind limb abduction and flat body posture. Surprisingly, WAY attenuated some aspects of locomotor activation and reduced the duration of hind limb abduction elicited by the agonist (5.1 Ϯ 0.9 versus 0.3 Ϯ 0.3 min for saline-or WAY-treated rats). These data indicate that 5-HT1A receptor stimulation in the PVN mediates the characteristic neuroendocrine response to serotonin agonist challenge. Moreover, they provide the first evidence that aspects of the behavioral serotonin syndrome are mediated by forebrain hypothalamic receptors.Measurements of hormone release and thermoregulatory responses to acute challenge with serotonergic releasing agents or clinically approved partial 5-HT1A receptor agonists have been used to assess the sensitivity of serotonergic function in patients suffering from various psychological disorders such as depression, obsessive compulsive disorder, or post-traumatic stress (Lesch et al., 1990a(Lesch et al., , 1991Flory et al., 1998;Rinne et al., 2000;Shapira et al., 2000). Administration of serotonin-releasing agents, as well as 5-HT1A receptor agonists, produces a distinct profile of stress hormone release characterized, in part, by increased plasma levels of adrenocorticotropin hormone (ACTH), prolactin, and cortisol in human subjects Sherman, 1984, 1985; Lesch et al., 1990a,b). Depressed patients demonstrate a blunted release of ACTH and cortisol in response to acute administration of partial 5-HT1A receptor agonists (Lesch et al., 1990a;Shapira et al., 2000). Positron emission tomography studies demonstrate reduced 5-HT1A receptor binding in several brain regions in both depressed patients as well as those diagnosed with panic disorder (Sargent et al., 2000;Neumeister et al., 2004). The...

A comparison of in vivo and in vitro neuroimaging of 5-HT1A receptor binding sites in the cat brain

“…Although the 5-HT 1A receptors are relatively few in these regions, recent data confirm that these receptors are implicated in the regulation of various physiological processes. It was notably reported that a subpopulation of 5-HT 1A receptors in the hypothalamus could play a regulatory role in neuroendocrine secretion (Osei-Owusu et al, 2005). Furthermore, electrophysiological studies have shown that selective 5-HT 1A receptor ligands modulate the activity of dopaminergic neurons in the substantia nigra (Dugast et al, 1998;Minabe et al, 2003).…”

Corticosteroid–serotonin interactions in the neurobiological mechanisms of stress-related disorders

“…Neuroanatomical studies also suggest an action of 5-HT through synaptic contacts between serotoninergic terminals and CRH-containing cells in the PVN (Liposits et al, 1987). Indeed, immunohistochemical investigations demonstrated the presence of 5-HT 1A receptors on PVN neurons, and microinjection of 8-OH-DPAT into this hypothalamic nucleus was shown to trigger ACTH secretion through local 5-HT 1A receptor activation (Zhang et al, 2004;Osei-Owusu et al, 2005). In contrast, somatodendritic 5-HT 1A autoreceptors are clearly not involved in the effects of 8-OH-DPAT as 5,7-dihydroxytryptamine lesions of the serotoninergic neurons, which eliminate such receptors, do not prevent ACTH release evoked by this agonist (Van de Kar et al, 1998).…”

Repeated Adolescent 3,4-Methylenedioxymethamphetamine (MDMA) Exposure in Rats Attenuates the Effects of a Subsequent Challenge with MDMA or a 5-Hydroxytryptamine1AReceptor Agonist

“…First, MDMA may alter the sensitivity of 5-HT 1A receptors in some areas of the brain and spinal cord (i.e., those areas responsible for 8-OH-DPAT elicitation of the serotonin syndrome) but not others (i.e., areas involved in 8-OH-DPAT-induced hypothermia). Investigators have traditionally believed that the serotonin syndrome is triggered at the level of the spinal cord or brainstem (Sternbach, 1991); however, recent results of Osei-Owusu et al (2005) suggest that at least some components of this syndrome, specifically hind limb abduction and low body posture, are mediated by 5-HT 1A receptors in the paraventricular nucleus of the hypothalamus. The location of the receptors involved in the hypothermic response to 8-OH-DPAT is controversial, with some investigators favoring a presynaptic localization (i.e., in the raphe nuclei) and others favoring a postsynaptic localization, possibly in the hypothalamus (see references cited in Aguirre et al, 1998).…”