Muscarinic M 4 receptor inhibition of dopamine D1-like receptor signalling in rat nucleus accumbens

Abstract

Several studies have indicated the occurrence of an antagonistic interaction between muscarinic and dopamine D1-like receptors in the ventral striatum, but the subtype(s) of muscarinic receptor involved has not been characterized. We show that in membranes of rat nucleus accumbens, carbachol inhibited the stimulation of adenylyl cyclase activity by dopamine and the dopamine D1-like receptor agonist (±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine without affecting the binding properties of dopamine to dopamine D1-like receptors. The carbachol inhibition was competitively counteracted by receptor antagonists with a rank order of potency typical of the involvement of the muscarinic M 4 receptor subtype. Moreover, muscarinic toxin 3, a selective muscarinic M 4 receptor antagonist, completely blocked the carbachol inhibition, whereas muscarinic toxin 7, a selective muscarinic M 1 receptor antagonist, had no effect. The muscarinic inhibition occurred to a similar extent in the core and shell regions. These data demonstrate that in nucleus accumbens, muscarinic M 4 receptors exert a direct inhibitory control on dopamine D1-like receptor signalling.