Borycz J

Degranulation and decrease in histamine levels of thalamic mast cells coincides with corticosterone secretion induced by compound 48/80

Mast cells (MC) synthesize and secrete numerous powerful mediators such as histamine (HA), serotonin and prostaglandins (PGs), which are known to have significant physiological effects on vascular and neuronal tissues. In the rat brain, H A is located in at least two different cell types: neurons and MC [1]. The quantitative importance of each of these two pools is still controversial. While there is a large body of evidence suggesting that neuronal H A is a neurotransmitter in the central nervous system, the specific functions carried out by HA of the MC present in brain structures remain speculative. Compound 48/80 a standard MC degranulating agent and H A releaser administered intracerebroventricularly (icv) decreased both the number of MC and the H A content of the crude nuclear fraction but not H A of the neuronal fraction [2]. HA is considered to be the hallmark mediator of MC activation. It is present in significant quantities in all MC so far examined and is stored in the cells cytoplasmic granules and released upon cell activation. Other MC mediators such as PGs are not stored but produced and secreted upon appropriate stimulation of the cells. Eicosanoid synthesis originates not only from phospholipid of damaged membranes but may also be the result of receptor-mediated granule exocytosis [3, 4]. The activation of MC granules triggers the arachidonic acid cascades resulting in PGs production and HA release [5]. The purpose of the present experiment was to determine and compare the extent of MC degranulation and changes in H A levels in the thalamus and hypothalamus with changes in the hypothalamicpituitary-adrenocorticol (HPA) activity after central administration of compound 48/80. A possible involvement of PGs induced by compound 48/80 on the HPA activation was also examined.

Social stress inhibits the nitric oxide effect on the corticotropin-releasing hormone- but not vasopressin-induced pituitary-adrenocortical responsiveness.

Putative involvement of endogenous nitric oxide (NO) in the corticotropin-releasing hormone (CRH, 1 microg/kg i.p.)- and vasopressin (AVP, 5 microg/kg i.p.)-induced ACTH and corticosterone secretion was investigated in both non-stressed and crowded rats. The NO synthase blocker Nomega-nitro-l-arginine (l-NNA, 2 mg/kg i.p. ) significantly augmented the AVP-induced ACTH and corticosterone secretion in control and stressed rats, but it increased the CRH-induced ACTH response only in control rats. Crowding stress did not affect the l-NNA evoked increase in AVP-induced hormone responses, but it abolished the CRH-induced ACTH response.

Crowding stress impairs the pituitary-adrenocortical responsiveness to the vasopressin but not corticotropin-releasing hormone stimulation.

To evaluate the effect of social crowding stress on the CRH and vasopressin-induced hypothalamic-pituitary-adrenocortical (HPA) response, both those neuropeptides were administered intracerebroventricularly and intraperitoneally to rats crowded for 3 days. Crowding stress did not affect the corticosterone response to CRH given by either route (1 micrograms i.c.v. or 2 micrograms/kg i.p.) but totally abolished or considerably diminished the response to vasopressin given i.p. (5 micrograms/kg) or i.c.v. (5 micrograms), respectively. Social crowding stress considerably impairs central vasopressin but does not change the CRH-system involved in the HPA stimulation.

Effect of indomethacin on the CRH- and VP-induced pituitaryadrenocortical response during social stress

The role of prostaglandins (PGs) on the corticotropin-releasing hormone (CRH)- and vasopressin (AVP)-induced pituitary-adrenocortical response under basal and social stress circumstances was investigated. Crowding stress applied for 3 days did not diminish the CRH-elicited corticosterone response, but it considerably reduced such a response to AVP. In control rats systemic or icv pretreatment with indomethacin, an inhibitor of PGs synthesis, did not affect the corticosterone response to ip or icv CRH administered 15 min later. By contrast, ip or icv pretreatment with indomethacin considerably reduced the corticosterone response to AVP given by either route in control rats. Similarly, ip pretreatment with indomethacin further reduced the corticosterone response to AVP already diminished by crowding stress. These results indicate that hypothalamic and anterior pituitary PGs are not involved in the CRH-elicited pituitary-adrenocortical response, but they significantly mediate this response to AVP under both basal and social stress circumstances.

Effect of crowding on corticosterone responses to central adrenergic stimulation

The social stress of crowding for 3, 7 and 14 days considerably reduced the increase in serum corticosterone elicited by intracerebroventricular administration of isoprenaline, a β-adrenergic agonist, on the 3rd and 7th days of crowding. The corticosterone response to clonidine, an α2-adrenergic agonist, was significantly diminished only after 3 days of crowding and this reduction was paralleled by a significant decrease in hypothalamic histamine content. The stimulatory effect of phenylephrine, an α2-adrenergic agonist, was not significantly changed by crowding stress. Social crowding stress caused almost total and persistent reduction in the hypothalamic-pituitary-adrenocortical (HPA) responsiveness to noradrenaline which stimulates the HPA axis via both α- and β-adrenergic receptors.

Effect of indomethacin on the pituitary-adrenocortical response to adrenergic stimulation

The role of prostaglandins (PGs) in stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by adrenergic agonists and catecholamines was investigated in nonanesthetized rats. The cyclooxygenase and PGs synthesis inhibitor indomethacin was given systemically or intracerebroventricularly (icv) 15 min prior to phenylephrine (30 micrograms), clonidine (10 micrograms), and isoproterenol (20 micrograms), an alpha 1-, alpha 2-, and beta-adrenergic receptor agonists, respectively, or noradrenaline (10 micrograms) and adrenaline (10 micrograms). Indomethacin given ip (2 mg/kg) or icv (10 micrograms) almost abolished the increase in corticosterone secretion elicited by phenylephrine, considerably reduced the response to clonidine but did not markedly affect the response to isoproterenol. Pretreatment with indomethacin by either route strongly suppressed the corticosterone response to noradrenaline, but did not substantially affect the hormonal response to adrenaline. The above data indicate that prostaglandins considerably mediate the HPA axis response to central stimulation of alpha 1- and alpha 2-, but not beta-adrenergic receptors. They also point to significant involvement of prostaglandins in the noradrenaline-, but not adrenaline-induced HPA axis predominantly via alpha 1-and alpha 2-adrenergic receptors, whereas adrenaline exerts stimulation manly via beta-adrenergic receptors.

Effect of social isolation on corticosterone secretion elicited by histaminergic stimulation

The effects of social stress of isolation for 3, 7, and 14 days on the responsiveness of the hypothalamic-pituitary-adrenocortical (HPA) axis to the stimulation of central histamine receptors and on the contents of hypothalamic biogenic amines were investigated.The corticosterone response to intraventricular administration of pyridylethylamine (PEA), a histamine H1-receptor agonist, was significantly higher in isolated than in control rats. The corticosterone response to dimaprit, a histamine H2-receptor agonist, tended to be slightly weaker in the stressed rather than in control rats.PEA significantly diminished the hypothalamic noradrenaline, dopamine and serotonin contents in both control and isolated rats. Dimaprit also decreased the brain NA, but not the DA concentrations in control and isolated rats. The changes in monoamines were not correlated with either the time, direction or magnitude of changes in corticosterone levels.These results suggest that hyperresponsiveness of the HPA system to the stimulation of central H1-histamine receptors during social isolation may depend on changes in the efficacy of H1 receptors but not on changes in the brain monoamine levels.

Pituitary-adrenocortical responsiveness to histaminergic stimulation during social stress of crowding in rats

Social stress of crowding for 3, 7, 14 and 21 days drastically reduces the serum corticosterone response to intracerebroventricular administration of dimaprit, a histamine H2-receptor agonist, moderately diminishes the response to pyridylethylamine, an H1-receptor agonist, and does not change significantly the corticosterone response to histamine.These results suggest that social stress of crowding considerably desensitizes central histamine H2-receptors involved in stimulation of the hypothalamic-pituitary-adrenal axis.

Influence of central neuronal histamine on the pituitary-adrenocortical activity stimulated by neurotransmitters

The effect of brain neuronal histramine and its receptors on monoaminergic stimulation of the hypothalamic-pituitary-adrenal (HPA) activity, measured indirectly through corticosterone secretion, was investigated in conscious rats. Pretreatment with α-fluoromethylhistidine, (α-FMH) a histamine synthesis inhibitor, did not markedly affect the increase in serum corticosterone levels induced by intracerebroventricular (icv) injection of muscimol, a GABAA receptor agonist and noradrenaline, an α- and β-adrenergic agonist, and slightly diminished the corticosterone response to isoprenaline, a β-adrenergic agonist. α-FMH totally abolished the increase in serum corticosterone induced by carbachol, a cholinergic muscarinic receptor agonist and significantly diminished the rise in corticosterone levels induced by clonidine, an α2-adrenergic agent. Pretreatment with the histamine receptor antagonists mepyramine and cimetidine also considerably reduced the carbachol-induced corticosterone response and the response induced by clonidine.These results indicate that brain neuronal histamine is considerably involved in stimulation of the HPA axis by cholinergic muscarinic and α2-adrenergic agonists, but not by GABAA and α1- and β-adrenergic agonists.

Effect of compound 48/80 on mast cells and histamine levels in rat brain and on corticosterone secretion

It is now well established that both histamine and serotonin are able to release corticotrophin releasing hormone (CRH) from the hypothalamic neurons and to stimulate the hypothalamic-pituitary-adrenocortical (HPA) axis [1, 2]. A significant part of brain histamine is contained not only in neurons but also in mast cells (MC) [3, 4]. It appeared that a neuronal histamine pool exhibits much faster turnover rate than MC histamine pool [5]. An inhibition of endogenous histamine synthesis by histidine decarboxylase inhibitor afluoromethylhistidine ( a-FMH) mainly inhibits the histamine synthesis in neurons but not in MC. The majority of brain mast cells are encountered in the thalamus [6] and their degranulation by compound 48/80 and release of histamine may activate the CRH-containing neurons. It is not clear to what extenta-FMH can affect the synthesis of histamine in brain MC and influence the compound 48/80-induced stimulation of the HPA axis. The purpose of the present study was to compare the effect of compound 48/80 given into the lateral cerebral ventricle (icv) on the thalamic MC degranulation, histamine content and the HPA axis activity. Also the effect of a-FMH on the compound 48/80-induced thalamic histamine level and corticosterone secretion was determined.