In vivo administration of an oligodeoxynucleotide antisense to the D2 dopamine receptor messenger RNA inhibits D2 dopamine receptor-mediated behavior and the expression of D2 dopamine receptors in mouse striatum.
A 20-mer phosphorothioate oligodeoxynucleotide (D2 antisense) to the D2 antisense dopamine receptor messenger RNA (mRNA) was administered i.c.v. to mice with unilateral 6-hydroxydopamine lesions of the corpus striatum. The mice were then challenged with acute injections of various agents that cause contralateral rotational behavior, and the levels of D1 and D2 dopamine receptors and their respective mRNAs were determined in the corpus striatum. Administering the D2 antisense inhibited rotations induced by the D2 dopamine receptor agonists quinpirole and N-propyl-N-2-thienylethylamine-5-hydroxytetralin but did not block rotations induced by the D1 dopamine receptor agonist 1-phenyl-2,3,4,5-tetrahydro-1H-3 benzazepine-7,8-diol HCl or by the muscarinic cholinergic receptor agonist oxotremorine. The reduction in quinpirole-induced rotational behavior was related to the amount and length of time the D2 antisense was given. Significant reductions in behavior were seen within 1 day of repeated injections of D2 antisense, and almost complete inhibition was seen after 6 days of treatment. Recovery from inhibition occurred by 2 days after cessation of antisense treatment. Repeated treatment with D2 antisense significantly reduced the levels of D2 dopamine receptors and D2 dopamine receptor mRNA, but not the levels of D1 receptors or D1 mRNA, in the dorsolateral area of the lesioned striatum. Treatment with an oligodeoxynucleotide with randomly placed nucleotides did not inhibit quinpirole-induced rotations or alter D2 dopamine receptors or D2 dopamine receptor mRNA in either area of striatum.(ABSTRACT TRUNCATED AT 250 WORDS)
Zhou
L W
LW
Department of Pharmacology, Medical College of Pennsylvania, Philadelphia.
Zhang
S P
SP
Qin
Z H
ZH
Weiss
B
B
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D001483:Base Sequence; D001522:Behavior, Animal / Q000187:drug effects*; D003342:Corpus Striatum / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004873:Ergolines / Q000494:pharmacology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D019257:Quinpirole; D012333:RNA, Messenger / Q000032:analysis*; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000502:physiology*; D012399:Rotation
D004873:Ergolines; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine