Acetylcholine potently stimulates the hypothalamic-pituitary-adrenal (HPA) axis. Cholinergic receptor agonist carbachol, given intraperitoneally (i.p.) or into the lateral cerebral ventricle (i.c.v.) to non-anesthetized rats acts via multiple pathways to stimulate the HPA axis. The present study sought to determine 1) the functional selectivity of carbachol for cholinergic muscarinic and/or nicotinic receptors involved in the stimulation of HPA axis; 2) the involvement of prostaglandins (PGs) generated by constitutive and inducible cyclooxygenase (COX-1 and COX-2) in the carbachol-induced ACTH and corticosterone secretion in non-stressed rats and animals exposed to social crowding stress for 7 days (24 per a cage for 6). Carbachol was given i.c.v. or i.p. and cholinergic receptor antagonists or cyclooxygenase isoenzyme antagonists were given by the same routes 15 min earlier. One hour after the last injection trunk blood was taken for ACTH and corticosterone determinations. Atropine (0.1 µg i.c.v.), a cholinergic receptor antagonist, totally abolished the carbachol (2 µg i.c.v.)-induced ACTH and corticosterone secretion and mecamylamine (20 µg i.c.v.), a selective nicotinic receptor antagonist, did not affect this secretion. This finding indicates that carbachol functions as a selective central cholinergic muscarinic receptor agonist for the HPA axis stimulation. Crowding stress significantly diminished the carbachol (0.2 mg/kg i.p.)-induced plasma ACTH and corticosterone levels measured 1 hr after administration. Pretreatment with indomethacin (2 mg/kg i.p.), a non-selective cyclooxygenase inhibitor, significantly diminished the ACTH and corticosterone responses to carbachol (0.2 mg/kg i.p.) in control rats and moderately decreased these responses in stressed rats. Piroxicam (0.2 and 2.0 mg/kg i.p.), a COX-1 inhibitor, considerably impaired the carbachol-induced ACTH and corticosterone responses in control rats and markedly diminished these responses in stressed rats. A selective COX-2 blocker, compound NS-398 (0.2 and 2.0 mg/kg i.p.), substantially decreased the carbachol-induced hormones secretion in control rats but did not markedly alter this secretion in stressed rats. These results indicate that in the carbachol-induced HPA axis activation PGs generated by COX-1 are considerably and to a much greater extent involved than PGs generated by COX-2. Social stress markedly diminishes the mediation of PGs generated by COX-1 but PGs synthesized by COX-2 do not substantially participate in the carbachol-induced HPA response.
The effect of γ-aminobutyric acid-receptor agonists, GABA and muscimol on the pituitary-adrenocortical activity, measured indirectly through corticosterone secretion, and the receptors involved were investigated in conscious rats. GABA given ip induced a dual effect, in lower dose (10mg/kg) it significantly decreased the resting serum corticosterone levels while in higher doses (100-500mg/kg) it considerably raised that level. Muscimol (0.5mg/kg ip) also increased the corticosterone concentration. Both GABA and muscimol given intracerebroventricularly (icv) induced a significant, dose-related increase in serum corticosterone levels. Bicuculline, a GABAA-receptor antagonist, totally abolished the corticosterone response to GABA but did not influence the response to muscimol. Pretreatment with atropine did not affect the corticosterone response to GABA but significantly diminished the response to muscimol. These results suggest that GABA moderately inhibits the pituitary-adrenal axis at the pituitary level but significantly stimulates it at the hypothalamic level. The stimulatory effect of GABA, but not muscimol, is mediated by hypothalamic GABA A-receptors, and in the effect of muscimol hypothalamic cholinergic, muscarinic receptors are involved to a significant extent.
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Acetylcholine is a transmitter in preganglionic autonomic and postganglionic parasympathetic nerves and a non-neuronal paracrine mediator in the alimentary tract. Acetylcholine is involved in the control of almost any function within these organ systems, and almost every cell type expresses multiple muscarinic receptor subtypes. Although muscarinic receptors at non-neuronal effector cells commonly are of the M3 subtype, the population usually consists of a mixture of muscarinic receptor subtypes often co-acting postsynaptically. However, the pattern of heterogeneity of varies between different tissues. The population in gland parenchymal tissue often consists of a mixture of M1 and M3 receptors, smooth muscle tissue of the gut of M2 and M3, blood vessels of M1, M3, M4 and M5 and neuronal cells of M1 and M4. Nitric oxide production, effects on inflammation and proliferation may involve M1, M3 and M5 receptors. Muscarinic receptors expressed on nerve terminals may indirectly modulate the responses by inhibition or facilitation of neuronal transmission in the autonomic nervous system. The present review describes signalling mechanisms, expression and functional effects of muscarinic receptors in salivary glands and in the gastrointestinal tract.