title: Alpha2-adrenoceptor modulation of cortical acetylcholine release in vivo.
abstract: Acetylcholine release in the rat cortex in vivo has been shown to be modulated by alpha2-adrenoceptor ligands. We have previously reported that the systemic administration of selective alpha2-antagonists including (+)-efaroxan increase, while alpha2-adrenoceptor agonists such as UK-14304 reduce the release of acetylcholine in the medial prefrontal cortex of conscious rats as measured by microdialysis. To evaluate the extent to which noradrenergic afferent inputs are required for the expression of these different effects, the present study examined the drug-induced changes in cortical acetylcholine release in rats which had undergone prior noradrenergic deafferentation. Rats were pretreated with the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (40 mg/kg, i.p.), which after three days had reduced noradrenaline levels in the medial prefrontal cortex by 84%. At that time, slices of cortex were incubated with [3H]choline, superfused and stimulated by consecutive exposures to increasing concentrations of K+. In N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine pretreated tissue, the [3H] outflows evoked by 20, 35 and 45 mM K+ were lower by 12%, 22% and 43%, respectively, in comparison to slices prepared from vehicle-pretreated control animals. For in vivo microdialysis experiments, rats were pretreated as above with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, or prepared seven to eight days in advance with bilateral 6-hydroxydopamine lesions of the locus coeruleus. Neither of these lesioning procedures significantly affected the basal outflow of endogenous acetylcholine in the cortex. In control rats, cortical acetylcholine outflow was increased by up to 300% of baseline values by (+)-efaroxan (0.63 mg/kg, i.p.), and was reduced to 21% of baseline by UK-14304 (2.5 mg/kg, i.p.), confirming our previous findings. In N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine pretreated rats, the inhibitory effect of UK-14304 on acetylcholine outflow persisted, while the ability of (+)-efaroxan to increase outflow was essentially eliminated. In locus coeruleus-lesioned rats, where cortical noradrenaline levels were reduced by 64%, (+)-efaroxan still increased acetylcholine outflow, but this effect was significantly attenuated and less sustained in comparison to sham-operated control rats. Viewed together with complimentary biochemical, electrophysiological and neuroanatomical evidence in the literature, a model is presented to account for these findings, and indicates that alpha2-adrenoceptors both on noradrenergic neurons (autoreceptors) and on non-noradrenergic cells (heteroreceptors) can participate in mediating drug-induced changes in medial prefrontal cortical acetylcholine release in vivo. The acetylcholine release-enhancing effect of (+)-efaroxan appears to be dependent on at least a partially intact cortical noradrenergic innervation.
authors.affiliation: Division de Neurobiologie I, Centre de Recherche Pierre Fabre, Castres, France.
authors.forename: S
authors.initials: S
authors.lastname: Tellez
authors.forename: F
authors.initials: F
authors.lastname: Colpaert
authors.forename: M
authors.initials: M
authors.lastname: Marien
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology*; D001596:Benzylamines / Q000494:pharmacology; D000068438:Brimonidine Tartrate; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004837:Epinephrine / Q000378:metabolism; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D010296:Parietal Lobe / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D013377:Substantia Innominata / Q000187:drug effects / Q000378:metabolism; D013566:Sympathomimetics / Q000494:pharmacology
chemical_list: C052414:1-(3,5-difluorobenzyl)imidazole-2-thiol; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D000959:Antihypertensive Agents; D001572:Benzofurans; D001596:Benzylamines; D007093:Imidazoles; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; D013566:Sympathomimetics; D000068438:Brimonidine Tartrate; C062597:efaroxan; D000109:Acetylcholine; C012102:DSP 4; D004837:Epinephrine