alpha(2)-adrenoceptor modulation of cortical acetylcholine release in vivo

Acetylcholine release in the rat cortex in vivo has been shown to be modula ted by alpha(2)-adrenoceptor ligands. We have previously reported that the systemic administration of selective alpha(2)-antagonists including (+)-efa roxan increase, while alpha(2)-adrenoceptor agonists such as UK-14304 reduc e the release of acetylcholine in the medial prefrontal cortex of conscious rats as measured by microdialysis. To evaluate the extent to which noradre nergic afferent inputs are required for the expression of these different e ffects, the present study examined the drug-induced changes in cortical ace tylcholine release in rats which had undergone prior noradrenergic deaffere ntation. Rats were pretreated with the noradrenergic neurotoxin N-(2-chloro ethyl)-N-ethyl-2-bromobenzylamine (40 mg/kg, i.p.), which after three days had reduced noradrenaline levers in the medial prefrontal cortex by 84%. Al that time, slices of cortex were incubated with [H-3]choline, superfused a nd stimulated by consecutive exposures to increasing concentrations of K+. In N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine pretreated tissue, the [H-3 ] outflows evoked by 20, 35 and 45 mM K+ were lower by 12%, 22% and 43%, re spectively, in comparison to slices prepared from vehicle-pretreated contro l animals. For in viva microdialysis experiments, rats were pretreated as a bove with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, or prepared seven t o eight days in advance with bilateral 6-hydroxydopamine lesions of the loc us coeruleus. Neither of these lesioning procedures significantly affected the basal outflow of endogenous acetylcholine in the cortex. In control rat s, cortical acetylcholine outflow was increased by up to 300% of baseline v alues by (+)-efaroxan (0.63 mg/kg, i.p.), and was reduced to 21% of baselin e 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 eff ect of UK-14304 on acetylcholine outflow persisted, while the ability of ()-efaroxan to increase outflow was essentially eliminated. In locus coerule us-lesioned rats, where cortical noradrenaline levels were reduced by 64%, (+)-efaroxan still increased acetylcholine outflow, but this effect was sig nificantly attenuated and less sustained in comparison to sham-operated con trol rats. Viewed together with complimentary biochemical, electrophysiolog ical and neuroanatomical evidence in the literature, a model is presented t o account for these findings, and indicates that alpha(2)-adrenoceptors bot h on noradrenergic neurons (autoreceptors) and on non-noradrenergic cells ( heteroreceptors) can participate in mediating drug-induced changes in media l prefrontal cortical acetylcholine release in vivo. The acetylcholine rele ase-enhancing effect of(+)-efaroxan appears to be dependent on at least a p artially intact cortical noradrenergic innervation. (C) 1999 IBRO. Publishe d by Elsevier Science Ltd.