Reduced expression of alpha2C-adrenoceptors in rat striatum following antisense oligodeoxynucleotide infusion.
The predominate subtypes of alpha2-adrenoceptors in the brain are alpha2A and alpha2C. The lack of selective ligands for these receptors hampers their functional characterization. We exploited an antisense strategy as an alternative pharmacological tool to study alpha2C-adrenoceptors. In rat striatum (caudate-putamen), alpha2-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 alpha2C-selective compound, prazosin, were fit best by a model assuming binding to two sites, presumably reflecting binding to alpha2A- and alpha2C-adrenoceptors. A 15-mer phosphorothioate oligodeoxynucleotide (alpha2C AS) complementary to the alpha2C-adrenoceptor mRNA, or a random sequence (RS) was administered to rats continuously for 4.5 days directly into the striatum. Compared to RS infusions, alpha2C AS infusions induced a 35% reduction in the Bmax of [3H]RX821002 in striatal homogenates (P < 0.05). Curves for the inhibition of [3H]RX821002 binding by prazosin were fit best by a model assuming a single interaction in alpha2C AS-infused rats and to a model assuming two sites in RS-infused rats. These results are consistent with the conjecture that both alpha2A- and alpha2C-adrenoceptors occur in the rat striatum and also demonstrate the feasibility of an antisense approach to examine the functional role of subtypes of alpha2C-adrenoceptors in the brain.
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Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson 39216, USA.
Ordway
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D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008297:Male; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects / Q000378:metabolism*
D016376:Oligonucleotides, Antisense; D018341:Receptors, Adrenergic, alpha-2; D011224:Prazosin