Intrastriatal administration of an oligodeoxynucleotide antisense to the D2 dopamine receptor mRNA inhibits D2 dopamine receptor-mediated behavior and D2 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 D2 dopamine receptor antisense oligodeoxynucleotide (D2 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 D2 antisense blocked the contralateral rotational behavior induced by the parenteral administration of the D2 dopamine receptor agonist quinpirole. The inhibitory effect of D2 antisense was dose- and time-related and was reversed upon cessation of D2 antisense treatment. This inhibitory effect was also selective in that D2 antisense treatment inhibited the rotational behavior induced by quinpirole but not that induced by the D1 dopamine receptor agonist SKF 38393 or by the muscarinic cholinergic agonist oxotremorine. Following repeated intrastriatal injections of D2 antisense into normal mice, parenteral administration of quinpirole caused rotational behavior ipsilateral to the side in which the D2 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 D2 antisense disappeared upon cessation of D2 antisense treatment. Repeated intrastriatal administration of D2 antisense also caused a significant reduction in the levels of D2, but not D1, dopamine receptors in striatum, as determined by receptor autoradiography. The levels of D2 dopamine receptors returned to normal upon cessation of D2 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 D2 dopamine receptors in striatum. These results show that selective inhibition of behavioral responses mediated by D2 dopamine receptors can be achieved by the direct injection of a D2 antisense oligodeoxynucleotide into a discrete brain area.
Zhou
L W
LW
Department of Pharmacology, Medical College of Pennsylvania, Philadelphia 19129, USA.
Zhang
S P
SP
Weiss
B
B
D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects*; D018491:Dopamine Agonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D007839:Functional Laterality; D008297:Male; D051379:Mice; D008845:Microinjections; D009043:Motor Activity / Q000187:drug effects*; D018721:Muscarinic Agonists / Q000494:pharmacology; D009498:Neurotoxins; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D016627:Oxidopamine; D019257:Quinpirole / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics*; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D012016:Reference Values; D012399:Rotation
D018491:Dopamine Agonists; D065127:Dopamine D2 Receptor Antagonists; D018721:Muscarinic Agonists; D009498:Neurotoxins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D016627:Oxidopamine