ALPHA(2C)-ADRENOCEPTORS MEDIATE INHIBITION OF FORSKOLIN-STIMULATED CAMP PRODUCTION IN RAT STRIATUM

The potential role of alpha(2)-adrenoceptors in modulating the activit y of adenylyl cyclase in the rat striatum was examined. The selective alpha(2)-adrenoceptor agonist, UK14,304, produced a concentration-depe ndent inhibition of forskolin-stimulated accumulation of cAMP in stria tal slices. The effect of UK14,304 was reversed by pre-incubation of s triatal slices with the selective alpha(2)-adrenoceptor antagonist, RX 821002, To determine whether alpha(2C)-adrenoceptors contribute to the alpha(2)-adrenoceptor-induced inhibition of forskolin-stimulated cAMP accumulation, an antisense oligodeoxynucleotide directed against alph a(2C)-adrenoceptor mRNA (alpha(2C)AS) or a random sequence (RS) was in fused directly into the striatum. The ability of alpha(2C)AS to reduce the expression of alpha(2C)-adrenoceptors has been previously demonst rated. alpha(2C)AS infusions did not reduce the ability of UK14,304 to inhibit forskolin-stimulated cAMP accumulation. Instead, alpha(2C)AS significantly enhanced forskolin-stimulated cAMP accumulation on the i nfusion side compared to the contralateral striatum. In contrast to th e effects of alpha(2C)AS, 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 RX 821002 could mimic the ability of alpha(2C)AS infusion to enhance fors kolin-stimulated cAMP accumulation, and did so in a concentration-depe ndent manner. alpha(2)-Adrenoceptors are negatively coupled to adenyly l cyclase in the rat striatum and alpha(2C)-adrenoceptors appear to be under tonic activation by an endogenous ligand in striatal slices. (C ) 1997 Elsevier Science B.V.