Reduced expression of alpha sub(2C)-adrenoceptors in rat striatum following antisense oligodeoxynucleotide infusion

The predominate subtypes of alpha 2-adrenoceptors in the brain are alpha 2A and alpha 2C. The lack of selective ligands for these receptors hampers their functional characterization. We exploited an antisense strategy as an alternative pharmacological tool to study alpha 2C-adrenoceptors. In rat striatum (caudate-putamen), alpha 2-adrenoceptors were characterized using the subtype-non-selective antagonist [3H]2-(2-methoxy-1,4-benzodioxan-2-yl)-2-imidazoline ([3H]RX821002). Specific [3H]RX821002 binding was saturable and to a single class of high-affinity sites. Curves for the inhibition of [3H]RX821002 binding by the alpha 2C-selective compound, prazosin, were fit best by a model assuming binding to two sites, presumably reflecting binding to alpha 2A- and alpha 2C-adrenoceptors. A 15-mer phosphorothioate oligodeoxynucleotide ( alpha 2CAS) complementary to the alpha 2C-adrenoceptor mRNA, or a random sequence (RS) was administered to rats continuously for 4.5 days directly into the striatum. Compared to RS infusions, alpha 2CAS infusions induced a 35% reduction in the Bmax of [3H]RX821002 in striatal homogenates (P