ANTISENSE OLIGODEOXYNUCLEOTIDE INHIBITS D(2)-DOPAMINE RECEPTOR-MEDIATED BEHAVIOR AND D(2)-MESSENGER RNA

There are several subtypes of dopamine receptors in the central nervous system9,26,28 which mediate the actions of dopamine in producing its diverse motor and behavioral effects.10,30 In this study we determined whether an antisense oligodeoxynucleotide directed to the mRNA encoding one of the subtypes of the dopamine receptor can inhibit a specific dopamine-mediated behavior. Accordingly, the effects of a phosphorothioate-modified antisense oligodeoxynucleotide targeted toward the D2 dopamine receptor mRNA (D2-antisense) was studied in mice with unilateral 6-hydroxydopamine-induced lesions of the corpus striatum. Rotational behavior in response to different agents, and the levels of D2 and D1 dopamine receptors and D2 and D1 dopamine receptor mRNAs in corpus striatum were then measured. In control mice, lesioning resulted in a contralateral rotational behavior in response to the D2 dopamine receptor agonist SKF 38393, the D2 dopamine agonist quinpirole, and the muscarinic cholinergic agonist oxotremorine. Lesioning also caused an increase in D2 dopamine receptor mRNA levels in the dorsolateral striatum. Intraventricular injections of the D2 antisense inhibited rotational behavior induced by quinpirole but not that induced by SKF 38393 or that induced by oxotremorine. Repeated administration of the D2 antisense significantly reduced the levels of the D2 dopamine receptor and D2 dopamine receptor mRNA in the dorsolateral but not the dorsomedial striatum. Similar treatment failed to significantly alter the levels of the D1 dopamine receptor or D1 receptor mRNA in dorsolateral or dorsomedial striatum. An oligodeoxynucleotide with randomly placed nucleotide sequences failed to alter rotational behavior in response to any of the agonists and failed to alter the levels of either the D1 or D2 dopamine receptors or their respective mRNAs in the striatum. The use of oligodeoxynucleotides antisense to transcript for the various dopamine receptor subtypes may prove useful for uncovering the behavioral effects that these receptors subserve.