Interaction of clonidine with pre- and post-synaptic adrenergic receptors of rat brain: effects on cyclic...

The locus and mechanism of interaction of clonidine with catecholamine-elicited accumulations of cyclic AMP has been investigated in brain slices from control and 6-hydroxydopamine-treated rats of the F-344 and Sprague-Daeley strains. The inhibitory effects of clonidine on the norepinephrine-stimulated accumulation of cyclic AMP and the potentiative effects of clonidine on the isoproterenol-stimulated accumulation of cyclic AMP are present to the same extent in cerebral cortical slices from control and 6-hydroxydopamine-treated Sprague-Dawley rats. Clonidine, at concentrations between 0.0001 and 100 muM has no intrinsic stimulatory activity on cortical cyclic AMP-generating systems from either control or 6-hydroxydopamine-treated rats. In F-344 rats phenoxybenzamine (100 muM) elicits a significant accumulation of cyclic AMP in cerebral cortical slices which can be abolished by pretreatment of rats with 6-hydroxydopamine, or by incubation of tissue slices with either clonidine or sotalol. The hyperresponsiveness to catecholamines usually observed following central administration of 6-hydroxydopamine failed to develop in the F-344 rat. Concentrations of phenoxybenzamine which have no significant stimulatory effects on cyclic AMP accumulation are capable of abolishing the potentiative effects of clonidine on the isoproterenol-stimulated formation of cyclic AMP. The beta-antagonist, sotalol, is a less effective antagonist of isoproterenol-stimulated accumulation of cyclic AMP in the presence of clonidine. Clonidine has no significant effect on the accumulation of cyclic AMP elicited by submaximal concentrations of isoproterenol in cerebellar slices. In toto, the data are consistent with the hypothesis that both the inhibitory effects on norepinephrine-stimulated accumulation of cyclic AMP and the stimulatory effects of clonidine on isoproterenol-elicited accumulation of cyclic AMP are exerted at postsynaptic alpha-adrenoceptors. No evidence was found for a presynaptic generation of cyclic AMP, although clonidine does reverse the stimulatory effects of phenoxybenzamine on cyclic AMP accumulation, presumably by interaction with a presynaptic site controlling norepinephrine release.