Effects of alpha 2-adrenoceptor agonists on locus coeruleus firing rate and brain noradrenaline turnover in N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)-treated rats.

Abstract

Previous studies have shown that a low dose of the alkylating compound N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) reduces the density of alpha 2-adrenoceptors in rat cerebral cortex and antagonizes the effects of an alpha 2-adrenoceptor agonist on noradrenaline release in rat cortical slices. In the present study, a corresponding dose of EEDQ (1 mg/kg, s.c., 24 h) was shown to reduce the effect of the alpha 2-adrenoceptor agonists clonidine and guanfacine on noradrenaline turnover in rat brain while not affecting the inhibitory effect of clonidine on locus coeruleus (LC) cell firing. When considerably higher doses of EEDQ were administered (10 and 20 mg/kg, s.c., 24 h) not only the biochemical but also the electrophysiological effects of clonidine were markedly reduced (or even reversed). The data support the notion the EEDQ decreases the responsiveness of brain alpha 2-adrenergic receptors; moreover, they indicate that alpha 2-adrenoceptors regulating LC activity are characterized by a larger receptor reserve or are less sensitive to the influence of alkylation than are the population of alpha 2-adrenoceptors regulating noradrenaline utilization.