INTRASTRIATAL ADMINISTRATION OF AN OLIGODEOXYNUCLEOTIDE ANTISENSE TO THE D-2 DOPAMINE-RECEPTOR MESSENGER-RNA 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 wh ether such antisense oligodeoxynucleotides could produce similar effec ts when injected into a discrete brain area. A D-2 dopamine receptor a ntisense 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 rot ational behavior induced by the parenteral administration of the D-2 d opamine receptor agonist quinpirole. The inhibitory effect of D-2 anti sense was dose- and time related and was reversed upon cessation of D- 2 antisense treatment. This inhibitory effect was also selective in th at D-2 antisense treatment inhibited the relational behavior induced b y quinpirole but not that induced by the D-1 dopamine receptor agonist SKF 38393 or by the muscarinic cholinergic agonist oxotremorine. Foll owing repeated intrastriatal injections of D-2 antisense into normal m ice, parenteral administration of quinpirole caused rotational behavio r ipsilateral to the side in which the D-2 antisense was injected. No such rotational behavior was seen when similarly treated mice were cha llenged with SKF 38393 or oxotremorine. The quinpirole-induced rotatio nal behavior in mice given intrastriatal injections of D-2 antisense d isappeared upon cessation of D-2 antisense treatment. Repeated intrast riatal administration of D-2 antisense also caused a significant reduc tion in the levels of D-2, but not D-1, dopamine receptors in striatum , as determined by receptor autoradiography. The levels of D-2 dopamin e receptors returned to normal upon cessation of D-2 antisense treatme nt. Intrastriatal administration of an oligodeoxynucleotide with rando mly placed nucleotides failed to alter the rotational response to quin pirole in either 6-hydroxydopamine-lesioned or normal mice and failed to alter the levels of D, dopamine receptors in striatum. These result s 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