M-1 AND M-2 MUSCARINIC RECEPTOR-MEDIATED INHIBITION OF DOPAMINE-SENSITIVE ADENYLATE-CYCLASE IN RAT NEOSTRIATUM - A PERMISSIVE ROLE FOR D-2 DOPAMINE-RECEPTORS

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  • 1 May 1988
    • journal article
    • research article
    • Vol. 245  (2) , 658-663
Abstract
The interactions between dopamine and muscarinic receptor subtypes coupled to adenylate cyclase in superfused rat neostriatal slices were investigated using the efflux of cyclic AMP, in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine, as a highly sensitive parameter of cyclic AMP production. Cyclic AMP efflux induced by simultaneous activation of (stimulatory) D-1 and (inhibitory) D-2 dopamine receptors by dopamine was reduced profoundly by the muscarinic receptor agonist oxotremorine and by inhibition of acetylcholinesterase with physostigmine, but not by the M-1 muscarinic receptor agonist McN-A-343. In contrast, upon blockade of D-2 receptors with (-)-sulpiride, dopamine-stimulated cyclic AMP efflux was inhibited by oxotremorine and physostigimine as well as by McN-A-343. Cyclic AMP efflux induced by isoprenaline, adenosine or vasoactive intestinal peptide was not affected by oxotremorine. the M-1 receptor-selective antagonist prenzepine, unlike the nonselective antagonist atropine, was about 10 times less potent in antagonizing the inhibitory effects of (a near-maximally effective concentration of) oxotremorine upon simultaneous D-1 and D-2 receptor activation that upon selective D-1 receptor activation (i.e., upon blockade of D-2 receptors). In the latter case, pirenzepine was about 5 times more effective as an antagonist when muscarinic receptors were activated by McN-A-343 than upon exposure of the slices to oxotremorine or physostigmine, wherease the potency of atropine was independent of the agonist used. When D-1 receptors were stimulated selectively, activation of M-1 receptors by McN-A-343 did not prevent a further inhibition of cyclic AMP efflux by oxotremorine, indicating the involvement of independent M-1 and M-2 receptor subtypes. Similar results were obtained when SKF 38393 and LY 171555 were used to activate D-1 and D-2 receptors, respectively. These data strongly suggest that blockade of D-2 receptors in the neostriatum with a neuroleptic drug amplifies the coupling of M-2 receptors, in addition to M-1 receptors, to dopamine-sensitive adenylate cyclase. Thus, upon selective D-1 receptor activation, the structurally different M-1 and M-2 receptors appear to be indistinguishable regarding their linkage to this effector system.

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