Stress-Induced Release of Anterior Pituitary Hormones: Effect of H₃ Receptor-Mediated Inhibition of Histaminergic Activity or Posterior Hypothalamic Lesion

Abstract

The effect of stress- or lipopolysaccharide (LPS) endotoxin-induced release of ACTH, β-endorphin (β-END) and prolactin (PRL) was investigated in two groups of conscious male rats: (1) Rats pretreated with different H₃ receptor agonists, which inhibit neuronal histamine (HA) synthesis and release, and (2) rats with bilateral posterior hypothalamic lesion, which destroys the histaminergic perikarya exclusively localized in the mammillary nuclei. The H₃ receptor agonists R(α)methyl-HA, BP 2-94 or imetit injected intraperitoneally (ip) had no effect on basal secretion of ACTH or PRL but inhibited the ACTH and PRL responses to restraint stress and the ACTH response to LPS endotoxin. LPS had no effect on PRL secretion. The inhibitory effect of the agonists was prevented by prior ip administration of the H₃ receptor antagonist thioperamide. Bilateral lesion of the posterior hypothalamus inhibited the ACTH, β-END and PRL responses to restraint stress, ether stress and LPS endotoxin, whereas sham operation had no effect compared to nonoperated control rats. In addition, posterior hypothalamic lesion inhibited the PRL response but not the ACTH and β-END responses to activation of serotonergic neurons induced by ip administration of the 5-HT precusor 5-hydroxytryptophan in combination with the 5-HT re-uptake inhibitor fluoxetine. Thus, serotonergic pathways were not damaged by the lesions. The present results support our previous findings that inhibition of neuronal HA synthesis by α-fluoromethylhistidine as well as blockade of H₁ or H₂ receptors inhibit the ACTH, β-END and PRL responses to stress and LPS endotoxin and further substantiate an important role of histaminergic neurons in the mediation of the stress-induced release of pituitary stress hormones. Furthermore, in accordance with our previous findings, the lesion experiments indicated the existence of an interaction between the histaminergic and serotonergic system in regulation of the stress- and LPS-induced PRL release.

Anxiolytic-like profiles of histamine H3 receptor agonists in animal models of anxiety: a comparative study with antidepressants and benzodiazepine anxiolytic

“…An intracerebroventricular infusion of histamine increased the level of CRF mRNA in the hypothalamic paraventricular nucleus (Kjaer et al 1998) and the subsequent release of ACTH and corticosterone into plasma (Kjaer et al 1994), suggesting positive regulation of CRF system by histamine. Moreover, stimulation of H3 receptor by R-α-methylhistamine, which is known to reduce the release of endogenous histamine (Ferretti et al 1998), inhibited the ACTH and prolactin responses to restraint stress (Knigge et al 1999). These observations enable us to propose that the putative mechanism of anxiolytic effects of H3 agonists depends on their functional modulation of CRF neurons via inhibition of histamine release.…”

Effect of blockade of postsynaptic H1 or H2 receptors or activation of presynaptic H3 receptors on catecholamine-induced stimulation of ACTH and prolactin secretion

“…However, although IME does cross the blood-brain barrier, IME and MEP/CIM may have different sites of action due to the different administration routes (IME ip vs MEP/CIM icv). Since we have previously found similar inhibitory effects on stimulated ACTH secretion of H1 and H2 receptor antagonists administered centrally and of H3 receptor agonists administered systemically (30,32,33), another explanation is more likely. It has been reported that H3 receptors, in addition to their presynaptic localization on histaminergic neurons are also located presynaptically on other aminergic or cholinergic neurons (34)(35)(36).…”

“…In contrast, pretreatment with the presynaptic H3 receptor agonist IME inhibited the ACTH response to E and NE. We have previously found that IME as well as other H3 receptor agonists inhibited the ACTH response to different stress stimuli (30), an effect that was prevented by concomitant administration of an H3 receptor antagonist. The difference between the lack of effect of the H1 and H2 receptor antagonists and the inhibitory effect of the H3 receptor agonist is difficult to explain, since similar actions were to be expected.…”

“…The catecholaminergic compounds E and NE were administered in an equimolar dose of 5 mmol icv. The doses of MEP (350 nmol icv) and CIM (400 nmol icv) have previously been found to inhibit HA-induced hormone release (26,29) and the dose of IME (2 mg/ kg ip) has been found to inhibit stress-induced hormone release (30).…”

Neuropharmacology of Histamine in Brain

“…In agreement they are activated during various forms of stress and heavily project to hypothalamic or limbic brain areas (e.g., amygdala or bed nucleus of the stria terminalis) involved in these responses. Various pharmacological studies have shown the participation of endogenous histamine via H 1 and H 2 receptor stimulation in the adrenocorticotropic hormone (ACTH), corticosterone, prolactin, or renin responses to stressful stimuli like restraint, endotoxin, or dehydration [507,508]. Furthermore, it seems that the activation of various subpopulations of histaminergic neurons within the tuberomammillary nucleus varies according to the nature of stressful stimuli [443,509].…”