title: Evidence for the involvement of presynaptic alpha-2 adrenoceptors in the regulation of norepinephrine metabolism in the rat brain.
abstract: In an attempt to evaluate the possible functional role of alpha-2 adrenoceptors located on noradrenergic nerve endings in the regulation of cerebral norepinephrine metabolism, we have measured the effects of clonidine and idazoxan on cerebral free 3,4-dihydroxyphenylethyleneglycol (DOPEG) levels (an index of norepinephrine turnover) in the rat after surgical and experimental manipulations that allow an exclusive interaction of the alpha-2 adrenergic agents with presynaptic alpha-2 autoreceptors. The possible contribution of distant (to cell bodies) transsynaptic feedback mechanisms triggered by stimulation of postsynaptic alpha-2 adrenoceptors and of somatodendritic alpha-2 autoreceptor-mediated regulatory mechanisms was eliminated by a local infusion of tetrodotoxin (50 ng) into the ascending noradrenergic bundle followed by electrical stimulation (at a frequency of 8 Hz) of this pathway distally to the neurotoxin injection site in chloral hydrate-anesthetized rats. Under these conditions, systemic injection of idazoxan (20 mg/kg i.p.) and clonidine (0.3 mg/kg i.p.) provoked an increase and a decrease, respectively, in free DOPEG levels in the hypothalamus, cerebral cortex and medial septum which were similar to those measured in naive rats. Moreover, in these animals the effect of idazoxan (1 mg/kg i.p.) was surmounted by a large dose of clonidine (0.3 mg/kg i.p.). The possible contribution of feedback mechanisms triggered by activation of postsynaptic alpha-2 adrenoceptors and mediated via local (to terminals) circuits (or a putative humoral agent released postsynaptically) was eliminated subsequently by a local injection of ibotenic acid in noradrenergic projection areas. Systemic administration of idazoxan (20 mg/kg i.p.) to ibotenate-lesioned rats elicited an increase in septal- and hypothalamic-free DOPEG levels comparable to that found in sham-operated rats. The effectiveness of the lesion was attested by a massive neuronal depopulation in the lesioned areas. Finally, ibotenic acid-induced destruction of noradrenergic target cells and local infusion of tetrodotoxin into followed by electrical stimulation of the ascending noradrenergic pathways were combined. Under these conditions, idazoxan still increased hypothalamic- and septal-free DOPEG levels, the extent of this alteration being similar to that found in normal rats. Altogether, these results suggest that irrespective of their low density, presynaptic alpha-2 autoreceptors play a cardinal role in the regulation of central nervous system norepinephrine metabolism.
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D003000:Clonidine / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D004558:Electric Stimulation; D007051:Ibotenic Acid / Q000494:pharmacology; D019329:Idazoxan; D008125:Locus Coeruleus / Q000378:metabolism / Q000502:physiology; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D004146:Dioxanes; D011942:Receptors, Adrenergic, alpha; D007051:Ibotenic Acid; D013779:Tetrodotoxin; D008734:Methoxyhydroxyphenylglycol; D003000:Clonidine; C010117:3,4-dihydroxyphenylglycol; D009638:Norepinephrine; D019329:Idazoxan