Intrastriatal administration of an oligodeoxynucleotide antisense to the D-2 dopamine receptor mRNA inhibits D-2 dopamine receptor-mediated behavior and D-2 dopamine receptors in normal mice and in mice lesioned with 6-hydroxydopamine

Previous studies have shown that the intracerebroventricular injection of antisense oligodeoxynucleotides targeted to the mRNAs encoding the different subtypes of dopamine receptors inhibited behaviors mediated by these receptors. The present studies were designed to determine whether such antisense oligodeoxynucleotides could produce similar effects when injected into a discrete brain area. A D-2 dopamine receptor antisense oligodeoxynucleotide (D-2 antisense) was repeatedly injected into one corpus striatum of either normal mice or mice with unilateral lesions of the striatum induced by 6-hydroxydopamine. In the latter, intrastriatal injection of D-2 antisense blocked the contralateral rotational behavior induced by the parenteral administration of the D-2 dopamine receptor agonist quinpirole. The inhibitory effect of D-2 antisense was dose- and time related and was reversed upon cessation of D-2 antisense treatment. This inhibitory effect was also selective in that D-2 antisense treatment inhibited the relational behavior induced by quinpirole but not that induced by the D-1 dopamine receptor agonist SKF 38393 or by the muscarinic cholinergic agonist oxotremorine. Following repeated intrastriatal injections of D-2 antisense into normal mice, parenteral administration of quinpirole caused rotational behavior ipsilateral to the side in which the D-2 antisense was injected. No such rotational behavior was seen when similarly treated mice were challenged with SKF 38393 or oxotremorine. The quinpirole-induced rotational behavior in mice given intrastriatal injections of D-2 antisense disappeared upon cessation of D-2 antisense treatment. Repeated intrastriatal administration of D-2 antisense also caused a significant reduction in the levels of D-2, but not D-1, dopamine receptors in striatum, as determined by receptor autoradiography. The levels of D-2 dopamine receptors returned to normal upon cessation of D-2 antisense treatment. Intrastriatal administration of an oligodeoxynucleotide with randomly placed nucleotides failed to alter the rotational response to quinpirole in either 6-hydroxydopamine-lesioned or normal mice and failed to alter the levels of D, dopamine receptors in striatum. These results show that selective inhibition of behavioral responses mediated by D-1 dopamine receptors can be achieved by the direct injection of a D, antisense oligodeoxynucleotide into a discrete brain area. Copyright (C) 1996 Elsevier Science Ltd