Influence of cyclooxygenase inhibitors on the central histaminergic stimulations of hypothalamic - pituitary - adrenal axis.

Brain histamine participates in central regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Endogenous prostaglandins modulate signal transduction of different neurotransmitters involved in activation of HPA axis. In the present experiment we investigated whether endogenous prostaglandins are involved in the stimulation of ACTH and corticosterone secretion by histaminergic systems in the rat brain. Histamine (50 microg), histamine-trifluoromethyl-toluidine derivative (HTMT, 75microg) a selective and potent H(1)-receptor agonist, and amthamine (50 microg) a H(2)-receptor agonist given intracerebroventricularly (i.c.v.) to non-anesthetized rats considerably increased ACTH and corticosterone secretion 1h after administration. A non-selective cyclooxygenase inhibitor indomethacin (2 mg/kg i.p. or 10 microg i.c.v.), piroxicam (0.02 and 0.2 microg i.c.v.) a more potent antagonist of constitutive cyclooxygenase (COX-1) and compound NS-398 (0.1 and 1.0 microg i.c.v.), a selective inhibitor of inducible cyclooxygenase (COX-2) were given 15 min before histamine and histamine receptor agonists. One hour after the last injection trunk blood from decapitated rats was collected for hormones determination. The histamine-induced ACTH and corticosterone secretion was significantly diminished by piroxicam and was not markedly altered by indomethacin and compound NS-398. The HTMT-elicited increase in ACTH and corticosterone secretion was significantly prevented by indomethacin and was not affected by piroxicam or compound NS-398. The amthamine-evoked increase in ACTH and corticosterone secretion was not markedly influenced by any cyclooxygenase blocker applied in the present experiment. These results indicate that the histamine H(1)-receptor transmitted central stimulation of the HPA axis is considerably mediated by prostaglandins generated by consititutive cyclooxygenase, whereas stimulation transmitted via H(2)-receptor does not significantly depend on endogenous prostaglandins mediation.

Effect of adrenergic antagonists and cyclooxygenase inhibitors on the nicotine-induced hypothalamic-pituitary-adrenocortical activity.

Nicotine is a potent stimulus for the hypothalamic-pituitary-adrenal (HPA) axis. Systemic nicotine acts via central mechanisms to stimulate by multiple pathways the release of ACTH from the anterior pituitary corticotrops and corticosterone from the adrenal cortex. Nicotine may stimulate indirectly the hypothalamic paraventricular nucleus, the site of the corticotropin-releasing hormone (CRH) neurons which activates ACTH release. In the present studies an involvement of adrenergic system and prostaglandins synthesized by constitutive cyclooxygenase (COX-1) and inducible cyclooxygenase (COX-2) in the nicotine-induced HPA response in rats was investigated. Nicotine (2.5-5 mg/kg i.p.) significantly increased plasma ACTH and corticosterone levels measured 1 hr after administration. Adrenergic receptor antagonists or COX inhibitors were injected i.p. 15 min prior to nicotine and the rats were decapitated 1 hr after the last injection. Prazosin (0.01-0.1 mg/kg), an alpha1-adrenergic antagonist, significantly decreased the nicotine-evoked ACTH and corticosterone secretion. Yohimbine (0.1-1.0 mg/kg), an alpha2-adrenergic antagonist, moderately diminished ACTH response, and propranolol (0.1-10 mg/kg), a beta-adrenergic antagonist, did not significantly alter the nicotine-induced hormones secretion. Pretreatment with piroxicam (0.2-2.0 mg/kg), a COX-1 inhibitor, considerably impaired the nicotine-induced ACTH and corticosterone secretion. Compound NS-398 (0.2-5.0 mg/kg), a selective COX-2 blocker did not markedly alter these hormones secretion, and indomethacin (2 mg/kg), a non-selective COX inhibitor significantly diminished ACTH response. These results indicate that systemic nicotine stimulates the HPA axis indirectly, and both adrenergic system and prostaglandins are significantly involved in this stimulation. Noradrenaline, stimulating postsynaptic alpha1-adrenergic receptors, and prostaglandins, synthesized by COX-1 isoenzyme, are of crucial significance in the nicotine-induced ACTH and corticosterone secretion.

Effect of social stress on COX-1 and COX-2-induced alterations in the adrenergic agonists-evoked hypothalamic-pituitary-adrenal responses.

The purpose of the present study was to investigate the contribution of prostaglandins (PGs) synthesized by constitutive (COX-1) and inducible (COX-2) cyclooxygenase to stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by adrenergic receptor agonists in rats under social crowing stress 3 days, (21 per a cage for 6) animals. The effects of phenylephrine, clonidine and isoprenaline, an alpha1-, alpha2- and beta-adrenergic agonist, respectively, in the presence and absence of COX-1 inhibitor, piroxicam, and COX-2 inhibitor, compound NS-398, on ACTH and corticosterone secretion in stressed rats were compared with these effects in non-stressed animals. All drugs were given intracerebroventricularly (i.c.v.), COX inhibitors 15 min before adrenergic agonists. Piroxicam (0.02 microg) and NS-398 (0.1 microg) significantly reduced the phenylephrine (30 microg) -induced ACTH and corticosterone secretion in both stressed and non-stressed rats. Piroxicam (0.02 microg) and NS-398 (0.01 microg) moderately decreased the clonidine (10 microg) -evoked hormone responses in control rats but did not alter these responses in stressed rats. Piroxicam (0.2 microg) and NS-398 (0.1 microg) moderately diminished the isoprenaline (20 microg) -evoked ACTH and corticosterone response in control rats, while in stressed rats these inhibitors did not significantly alter the isoprenaline-induced rise in ACTH and corticosterone secretion. These results indicate that in hypothalamic structures involved in the regulation of adrenergic agonists-induced HPA stimulation COX-2 is expressed under physiological synaptic activity. Social crowding stress does not alter the significant involvement of prostaglandins in the HPA response induced by stimulation of central alpha1-adrenergic receptors. Prostaglandins are of lesser importance in activation of the HPA axis by alpha2- and beta-adrenergic receptors under basal and social stress conditions.

Involvement of constitutive (COX-1) and inducible cyclooxygenase (COX-2) in the adrenergic-induced ACTH and corticosterone secretion.

The involvement of prostaglandins synthesized by constitutive (COX-1) and inducible cyclooxygenase (COX-2) in central stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by adrenergic receptor agonists was investigated in conscious rats. COX-1 and COX-2 inhibitor, piroxicam (0.02 and 0.2 microg) and compound NS-398 (0.01 and 0.1 microg), respectively, were given intracerebroventricularly (i.c.v.) 15 min prior to i.c.v. adrenergic receptor agonists: phenylephrine (30 microg) and clonidine (10 microg), an alpha1- and alpha2-adrenergic agonist, and isoprenaline (20 microg) a non-selective beta-adrenergic agonist and clenbuterol (10 microg) a selective beta2-adrenergic agonist. Piroxicam and NS-398 considerably and dose-dependently reduced the phenylephrine-induced increase in ACTH and corticosterone secretion. Pretreatment with piroxicam and NS-398 markedly impaired the clonidine-evoked ACTH and corticosterone secretion. Piroxicam moderately diminished the isoprenaline-elicited increase in ACTH and corticosterone, while NS-398 did not markedly alter ACTH secretion. The clenbuterol-induced ACTH and corticosterone responses were considerably impaired by pretreatment with piroxicam, and slightly less potently by NS-398. These results indicate that in central structures involved in regulation of the HPA axis both constitutive and inducible cyclooxygenase are present under normal conditions in rats. These isoenzymes are significantly involved in the stimulatory signaling transduced by postsynaptic alpha1-adrenergic receptors and, to a lesser extent, by alpha2-adrenergic receptors. Both isoenzymes affect moderately the stimulatory action of a non-selective beta-adrenergic agonist on ACTH and corticosterone secretion. COX-1 participates considerably and COX-2 markedly in the potent stimulatory action of selective beta2-adrenergic receptors on HPA axis.

The influence of indomethacin on the acth secretion induced by central stimulation of adrenergic receptors.

We had previously demonstrated that indomethacin affected the corticosterone secretion induced by central stimulation of alpha-but not beta-adrenergic receptors in conscious rats. In the present study we investigated whether hypothalamic and/or pituitary prostaglandins (PGs) were involved in the central adrenergic stimulation of ACTH secretion. Indomethacin, 2 mg/kg ip or 10 microg intracerebroventricularly (icv), was administered 15 min before phenylephrine (30 microg icv), an alpha-adrenergic agonist, clonidine (10 microg), an alpha2-adrenergic agonist, and isoprenaline (20 microg) or clenbuterol (10 microg), a beta1- or beta2-adrenergic agonist. One hour after the last injection the rats were decapitated and plasma levels of ACTH were measured. The present results show that the ACTH responses induced by icv administration of phenylephrine and clonidine were considerably impaired by icv or ip pretreatment with indomethacin, an inhibitor of prostaglandin synthesis. Indomethacin given by either route only slightly diminished the isoprenaline-induced ACTH response and did not substantially alter the clenbuterol-induced response. The adrenergic-induced ACTH responses were more potently inhibited by ip than by icv pretreatment with indomethacin, which may result from a stronger inhibition of PGs synthesis in the median eminence and anterior pituitary by ip pretreatment with indomethacin than in hypothalamic structures by its icv administration. These results indicate a significant involvement of PGs in central stimulation of the hypothalamic-pituitary adrenal (HPA) axis by alpha1- and alpha2- but not beta-adrenergic receptors.

Involvement of nitric oxide in central histaminergic stimulation of the hypothalamic-pituitary-adrenal axis.

Brain histamine participates in central regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Endogenous nitric oxide (NO) modulates signal transduction of some neurotransmitters involved in activation of the HPA axis. In the present study we investigated whether endogenous NO and histaminergic systems in the rat brain interact in their regulation of ACTH and corticosterone secretion. Histamine (50 microg), histamine-trifluoromethyl-toluidide derivative (HTMT, 75 microg) a selective and potent H1-receptor agonist, and amthamine (75 microg) a H2-receptor agonist given intracerebroventricularly (i.c.v.) considerably increased ACTH and corticosterone secretion 1 h after administration. A potent and competitive inhibitor of rat brain neuronal NO synthase, (NOS), 7-nitroindazole (7-NI), given i.p. 15 min before histamine moderately increased the histamine-induced ACTH secretion and did not substantially alter the histamine-induced corticosterone secretion. Pretreatment with 7-NI totally abolished the HTMT-induced increase in ACTH and corticosterone secretion. The amthamine-evoked rise in ACTH secretion was moderately diminished and the amthamine-induced corticosterone secretion was not substantially altered by preatreatment with 7-NI. These results suggest that the histamine H -receptor transmited central stimulation of the HPA axis is considerably mediated by endogenous NO, whereas stimulation by histamine and via H2-receptor does not significantly depend on endogenous NO mediation.

Blockade of nitric oxide formation impairs adrenergic-induced ACTH and corticosterone secretion.

It has been suggested that adrenergic agents might modulate the L-arginine-NO pathway. Sympathomimetic agonists enhance the basal release of NO, and noradrenaline increases the synthesis of nitric oxide synthase (NOS) in the medial basal hypothalamus in vitro. In the present study possible involvement of NO in central stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by adrenergic agents was investigated in conscious rats. The nitric oxide synthase blocker N(omega)-nitro-L-arginine methyl ester (L-NAME 2 and 10 microg) was administered intracerebroventricularly (i.c.v.) 15 min before the adrenergic agonist given by the same route; 1 h later the rats were decapitated. Plasma levels of ACTH and corticosterone were measured. L-NAME significantly diminished the ACTH and corticosterone response to phenylephrine (30 microg), an alpha1-adrenergic receptor agonist. These hormone responses to clonidine (10 microg), an alpha2-receptor agonist, were dose-dependently suppressed or totally abolished by L-NAME. A significant rise in the ACTH and corticosterone secretion induced by isoprenaline (10 microg), a beta-adrenergic receptor agonist, was only moderately diminished by pretreatment with L-NAME. These results indicate that NOS is considerably involved in central stimulation of the HPA axis by alpha1- and alpha2-adrenergic receptor agonists, and that NO mediates the stimulatory action of these agonists on ACTH and corticosterone secretion. The stimulation induced by beta-adrenergic receptors is only moderately affected by endogenous NO.

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.

Effect of indomethacin on nicotine-induced ACTH and corticosterone response.

The effect of nicotine on ACTH and corticosterone secretion and possible mediation of prostaglandins in this secretion was investigated in conscious rats. Nicotine (5 and 10 mg/kg i.p.) considerably increased the plasma ACTH and corticosterone levels, measured 1h after injection. Mecamylamine (10 and 50 micrograms i.c.v.), a nicotinic receptor antagonist, given 15 min prior to nicotine dose-dependently diminished the ACTH and corticosterone responses, by 59 and 30% respectively. Pretreatment with hexamethonium (2 mg/kg i.p.), a peripheral blocker of nicotinic receptors, diminished to a similar extent the nicotine-induced ACTH and corticosterone responses. On the other hand atropine, a muscarinic receptor antagonist, did not markedly alter those responses. Systemic or intracerebroventricular pretreatment with indomethacin (2 mg/kg i.p. or 0.1 and 1 microgram i.c.v.), a cyclooxygenase and endogenous prostaglandin synthesis blocker considerably reduced, by 58%, the nicotine-induced ACTH response, but did not alter the corticosterone response. These results show that nicotine given systemically stimulates ACTH and corticosterone secretion by selective activation of central and peripheral acetylcholine nicotinic receptors. Endogenous prostaglandins are significantly involved in the nicotine-induced central stimulation of ACTH secretion. Prostaglandins do not directly affect the nicotine-induced corticosterone secretion from the adrenal cortex.

Effect of L-NAME, a specific nitric oxide synthase inhibitor, on corticotropin-releasing hormone-elicited ACTH and corticosterone secretion.

This study was designed to determine the role of endogenous nitric oxide (NO) in the corticotropin-releasing hormone (CRH)-induced ACTH and corticosterone secretion, as well as possible involvement of hypothalamic dopamine and noradrenaline in that secretion in conscious rats. CRH given i.p. stimulated dose-dependently the pituitary-adrenocortical activity measured 1 h later. Dexamethasone (0.2 mg/kg i.p.) injected 1 h before CRH (1 microg/kg i.p.) totally abolished the CRH-elicited ACTH and corticosterone secretion, indicating a predominantly pituitary site of CRH-evoked stimulation. L-arginine (120 mg/kg i.p.) and N(omega)-nitro-L-arginine methyl ester (L-NAME 5-10 mg/kg i.p.) did not markedly affect the basal plasma ACTH and corticosterone levels. L-NAME given 15 min before CRH markedly, but not significantly, augmented the CRH-induced ACTH response, and enhanced more potently and significantly the corticosterone response. Pretreatment with L-arginine, a substrate for NOS, slightly diminished the CRH-induced ACTH response and considerably reduced the corticosterone response. L-arginine also significantly reversed the L-NAME-evoked increase in the CRH-induced ACTH and corticosterone secretion. L-NAME did not markedly alter the CRH-induced hypothalamic dopamine and noradrenaline levels, while L-arginine significantly increased noradrenaline level. However, those alterations were not directly correlated with the observed changes in ACTH and corticosterone secretion. These results indicate that in conscious rats NO plays a marked inhibitory role in the CRH-induced ACTH secretion and inhibits more potently corticosterone secretion. Hypothalamic dopamine and noradrenaline do not seem to be directly involved in the observed alterations in ACTH and corticosterone secretion.

Influence of nitric oxide synthase inhibitors on the vasopressin-induced pituitary-adrenocortical activity and hypothalamic catecholamine levels.

In the present study the role of endogenous nitric oxide (NO) in the vasopressin-induced ACTH and corticosterone secretion was investigated in conscious rats. Vasopressin (AVP 5 microg/kg i.p.) considerably augmented ACTH and corticosterone secretion. L-arginine (120 and 300 mg/kg i.p.) did not significantly alter the AVP-induced secretion of those hormones. Nitric oxide synthase (NOS) blockers N(omega)-nitro-L-arginine (L-NNA) and its methyl ester (L-NAME) given i.p. 15 min before AVP markedly increased the AVP-induced ACTH secretion. L-NNA (2 mg/kg) more potently and significantly increased the AVP-induced ACTH secretion, whereas L-NAME elicited a weaker and not significant effect. Both those NOS antagonists intensified significantly and to a similar extent the AVP-induced corticosterone secretion. L-arginine (120 mg/kg i.p.) reversed the L-NNA-induced rise in the AVP-stimulated ACTH secretion and substantially diminished the accompanying corticosterone secretion. Neither vasopressin alone nor in combination with L-arginine and L-NAME evoked any significant alterations in the hypothalamic noradrenaline and dopamine levels. L-NNA (2 and 10 mg/kg i.p.) elicited a dose dependent and significant decrease in the hypothalamic noradrenaline level. The hypothalamic dopamine level was not significantly altered by any treatment. These results indicate that in conscious rats endogenous NO has an inhibitory influence on the AVP-induced increase in ACTH and corticosterone secretion. L-NNA is significantly more potent than L-NAME in increasing the AVP-induced ACTH secretion. This may be connected with a considerable increase by L-NNA of hypothalamic noradrenergic system activation which stimulates the pituitary-adrenal axis in addition to specific inhibition of NOS.

Mediation by nitric oxide of the carbachol-induced corticosterone secretion in rats.

Nitric oxide synthase, an enzyme responsible for nitric oxide (NO) formation has been found in the hypothalamic paraventricular nucleus and median eminence, structures closely associated with regulation of the pituitary activity, and the pituitary gland itself. Nitric oxide modulates the stimulated release of CRH from the rat hypothalamus in vitro, which suggests its role in regulating the secretion of ACTH from the pituitary corticotrops and of corticosterone from the adrenal cortex. The purpose of the present study was to elucidate the yet unknown role of endogenous NO in the HPA response to central cholinergic stimulation in conscious rats. Neither L-arginine an NO precursor, nor the NO synthase blockers N omega-nitro-L-arginine methyl ester (L-NAME) and N omega-nitro-L-arginine (L-NNA) caused any consistent changes in the basal serum corticosterone levels. L-arginine, given in higher doses (120-150 mg/kg ip) 15 min prior to icv carbachol (2 micrograms), markedly diminished the carbachol-induced rise in corticosterone secretion. Systemic pretreatment with the nitric oxide synthase inhibitor L-NAME (5 mg/kg) significantly raised the carbachol-elicited corticosterone response, while addition of L-arginine completely blocked the effect of L-NAME. A similar increase in the carbachol-induced corticosterone response was produced by icv pretreatment with L-NAME (2 micrograms), indicating a central site of the NO interaction with cholinergic stimulation of the HPA response. L-NAME is a weak inhibitor of neuronal NOS itself, and must first be de-estrified to N omega-nitro-L-arginine to potently inhibit this enzyme. Systemic (10 mg/kg) and icv (1 microgram) pretreatment with L-NNA enhanced more effectively the carbachol-induced rise in corticosterone secretion than did pretreatment with L-NAME by either route. These results are the first direct evidence that endogenous NO significantly inhibits the HPA response to central cholinergic, muscarinic receptor stimulation under in vivo conditions.

Role of nitric oxide in the vasopressin-induced corticosterone secretion in rats.

The presence of nitric oxide synthase (NOS) in hypothalamic structures which control the activity of the hypothalamic-pituitary-adrenal (HPA) axis suggests a role for NO in regulation of ACTH and corticosterone secretion. We investigated the involvement of NO in the corticosterone secretion induced by vasopressin (AVP), a potent coregulator of the HPA activity. AVP injected i.p. was, on a molar basis, considerably more potent than administered intracerebroventricularly in inducing corticosterone secretion. This finding suggests a preferential action of AVP on pituitary corticotrop receptors, but not on central structures involved in stimulation of the HPA axis. Dexamethasone given before AVP totally abolished the AVP-elicited corticosterone response by a feedback mechanism and/or inhibition of the phospholipase A2 activity and prostaglandin synthesis. Pretreatment with the NOS inhibitors L-NAME and L-NNA augmented significantly and to a similar extent the corticosterone response to AVP administered both systemically and centrally and L-NNA was found to be more potent in this respect. Pretreatment with L-arginine markedly reduced the AVP-induced corticosterone response. These results suggest that endogenous nitric oxide is significantly involved in the AVP-elicited corticosterone secretion and NO-induced alterations in the prostaglandin synthesis may participate in this action.

Central histaminergic mechanisms mediate the vasopressin-induced pituitary adrenocortical stimulation.

Involvement of histamine receptors and hypothalamic and hippocampal histamine in stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by vasopressin (AVP) was investigated in conscious rats. The HPA activity was assessed by measuring serum corticosterone levels. One hour after administration AVP, (5 micrograms/kg) given i.p. significantly raised the serum corticosterone and hippocampal histamine levels, while the hypothalamic histamine content was not affected. Pretreatment with the inhibitor of the brain histamine synthesis alpha-fluoromethylhistidine (alpha-FMH) (50 mg/kg i.p.) considerably reduced both the AVP-elicited serum corticosterone response and the hypothalamic and hippocampal histamine levels. The histamine H1- and H2-receptor-antagonists mepyramine (0.01 mg/kg) and ranitidine (0.1 mg/kg), given ip 15 min prior to AVP, significantly impaired the AVP-induced rise in the serum corticosterone level and totally abolished the AVP-elicited increase in the histamine content in the hippocampus; moreover mepyramine significantly lowered this content in hypothalamus. Pretreatment with the histamine H3-receptor antagonist thioperamide (5 mg/kg i.p.) also significantly decreased the AVP-elicited corticosterone response, but did not alter the histamine content in either brain structure examined. These results indicate that central histamine H1-, H20 and H3-receptors significantly mediate the stimulatory action of AVP on the pituitary-adrenocortical axis. Hippocampal histamine may be involved in mediation of the AVP-induced effect via H1- and H2-receptors. The inhibitory effect of thioperamide seems to be located directly at non H3-intracellular sites of the pituitary-adrenocortical axis.

The role of prostaglandins and the hypothalamic and hippocampal histamine in the clonidine-induced pituitary-adrenocortical response.

Involvement of prostaglandins (PGs) and histamine in the hypothalamus and hippocampus in the clonidine-induced pituitary-adrenocortical response was investigated in conscious rats. The hypothalamic-pituitary adrenocortical (HPA) activity was assessed indirectly by measuring corticosterone secretion. Clonidine, an alpha 2-adrenergic agonist, given intracerebroventricularly (10 micrograms icv), considerably increased the serum corticosterone and hypothalamic histamine levels and markedly elevated the hippocampal histamine levels. Systemic or icv pretreatment with indomethacin (2 mg/kg or 10 micrograms), an inhibitor of prostaglandin synthesis, significantly reduced the clonidine-induced corticosterone response and abolished the increase in the hypothalamic and hippocampal histamine levels elicited by clonidine. Indomethacin in the doses used did not substantially change the resting serum corticosterone or hypothalamic and hippocampal histamine levels. These results indicate that prostaglandins and hypothalamic histamine are considerably involved in the HPA response to alpha 2-adrenergic receptor stimulation. They also suggest involvement of prostaglandins and histamine of the hippocampus in the clonidine-induced HPA response.

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 indomethacin on the CRH- and VP-induced pituitary-adrenocortical 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.

Adrenergic regulation of the hypothalamic-pituitary-adrenal axis under basal and social stress conditions.

The significance of adrenergic neurons and anterior pituitary and hypothalamic adrenergic receptors in stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by corticotropin releasing hormone (CRH) and vasopressin (AVP) was investigated under basal conditions and after three-days crowding stress in conscious rats. In nonstressed rats the corticosterone response to phenylephrine, an alpha 1-adrenergic receptor agonist, was totally abolished or considerably reduced by prazosin, an alpha 1-receptor antagonist, when both those drugs were given ip or icv, respectively. The corticosterone response to ip isoproterenol, a beta-adrenergic agonist, was abolished by icv or ip pretreatment with propranolol, a beta-adrenergic receptor antagonist. These results indicate involvement of functional alpha 1-adrenoceptors in the hypothalamus and anterior pituitary corticotrops and pituitary beta-adrenoceptors in stimulation of the HPA axis. AVP given ip was almost as potent as CRH in stimulating corticosterone secretion. The stimulatory effect of AVP given ip or icv on corticosterone secretion was significantly diminished by propranolol, but not prazosin or yohimbine, indicating an involvement of beta-adrenergic receptors. The specific noradrenergic neurotoxin DSP-4, given ip 11 days before the experiment, considerably diminished the hypothalamic noradrenaline (NA) level but did not influence the resting and icv CRH- or AVP-stimulated corticosterone secretion. In nonstressed rats CRH further enhanced significantly the DSP-4-elicited fall in hypothalamic NA, whereas AVP almost totally prevented that decrease. In stressed rats CRH considerably antagonized the DSP-4-induced decrease in the hypothalamic NA level while AVP did not affect that decrease. The CRH- and AVP-elicited changes in hypothalamic NA were not correlated with changes in corticosterone secretion. Tree-day crowding stress did not affect the CRH-induced corticosterone secretion, whereas it considerably reduced the AVP-evoked corticosterone response. These results indicate that pituitary and hypothalamic adrenergic receptors are significantly involved in the AVP- and CRH-induced HPA axis stimulation, but the hypothalamic NA level, though modified by these peptides, does not significantly influence the HPA 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.