Abstract

The effects of intracerebroventricular (i.c.v.) administration of a 20-mer phosphorothioate oligodeoxynucleotide antisense to the D1 dopamine receptor mRNA (D1 antisense) on D1 dopamine receptor-mediated behaviors were studied in normal mice and in mice with unilateral 6-hydroxydopamine-induced lesions of corpus striatum. Treating mice with D1 antisense inhibited grooming behavior induced by the D1 dopamine receptor agonist SKF 38393 [1-phenyl-2,3,4,5-tetrahydro-1H-3 benzazepine-7,8-diol hydrochloride], the reduction in grooming being related to the amount and length of time D1 antisense was given, with significant reductions in grooming behavior observed within 2 days of repeated injections of D1 antisense. Administering D1 antisense also inhibited rotational behavior induced by SKF 38393 in mice with unilateral 6-hydroxydopamine-induced lesions of corpus striatum. This inhibitory effect on rotational behavior could not be overcome by increasing the dose of SKF 38393. Recovery from inhibition of both grooming and rotational behaviors occurred after cessation of D1 antisense treatment. An oligomer with a similar composition of bases but placed in a random sequence failed to alter grooming or rotational behaviors induced by SKF 38393. In contrast to its effects on D1-mediated behaviors, treatment with D1 antisense had no significant inhibitory effect on stereotyped behavior induced by the D2 dopamine receptor agonist quinpirole [trans-(-)-4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H(or 2H)-pyrazolo- (3,4g)-quinoline dihydrochloride] in normal mice and produced no significant inhibition of rotational behavior induced either by quinpirole or by the muscarinic cholinergic agonist oxotremorine in 6-hydroxydopamine-lesioned mice.(ABSTRACT TRUNCATED AT 250 WORDS)