α2C-Adrenoceptors mediate inhibition of forskolin-stimulated cAMP production in rat striatum

Abstract

The potential role of α 2-adrenoceptors in modulating the activity of adenylyl cyclase in the rat striatum was examined. The selective α 2-adrenoceptor agonist, UK14,304, produced a concentration-dependent inhibition of forskolin-stimulated accumulation of cAMP in striatal slices. The effect of UK14,304 was reversed by pre-incubation of striatal slices with the selective α 2-adrenoceptor antagonist, RX821002. To determine whether α 2C-adrenoceptors contribute to the α 2-adrenoceptor-induced inhibition of forskolin-stimulated cAMP accumulation, an antisense oligodeoxynucleotide directed against α 2C-adrenoceptor mRNA ( α 2CAS) or a random sequence (RS) was infused directly into the striatum. The ability of α 2CAS to reduce the expression of α 2C-adrenoceptors has been previously demonstrated. α 2CAS infusions did not reduce the ability of UK14,304 to inhibit forskolin-stimulated cAMP accumulation. Instead, α 2CAS significantly enhanced forskolin-stimulated cAMP accumulation on the infusion side compared to the contralateral striatum. In contrast to the effects of α 2CAS, infusions of RS had no effects on forskolin-stimulated cAMP accumulation or on the ability of UK14,304 to inhibit this effect. Incubation of striatal slices from untreated rats with RX821002 could mimic the ability of α 2CAS infusion to enhance forskolin-stimulated cAMP accumulation, and did so in a concentration-dependent manner. α 2-Adrenoceptors are negatively coupled to adenylyl cyclase in the rat striatum and α 2C-adrenoceptors appear to be under tonic activation by an endogenous ligand in striatal slices.