Effects of intrastriatal infusion of D-2 receptor antisense oligonucleotide on apomorphine-induced behaviors in the rat

An antisense oligonucleotide strategy was employed to specifically deplete postsynaptic striatal D-2 receptors in order to determine the possible role of presynaptic D-2 autoreceptors in mediating behavioral responses induced by low doses of apomorphine. A phosphorothioate-modified antisense oligonucleotide complementary to the first 19 bases of the coding region of D-2 receptor mRNA, a scrambled sequence comprising the same bases, or saline was infused bilaterally into the striatum of adult rats, twice daily for 2 days via indwelling cannulae. After an interval of 8-12 h, rats were habituated and challenged with high (300 mu g/kg; subcutaneous) or low (50 mu g/kg; s.c.) doses of apomorphine or its vehicle (0.1% ascorbic acid). Yawning, vacuous chewing mouth movements, hypoexploration, and penile grooming induced by low-dose apomorphine were unaffected by antisense infusion into the striatum, whereas stereotypic sniffing following high-dose apomorphine was markedly suppressed. Intrastriatal infusion of antisense resulted in significantly diminished [H-3]-raclopride binding, while binding of [H-3]-SCH 23390 (D-1 receptors) and [H-3]-WIN 35428 (dopamine transporter) was unchanged. D-2 mRNA levels determined by quantitative in situ hybridization were normal in the striatum and the substantia nigra. Our results confirm that stereotypic sniffing is mediated via postsynaptic D-2 receptors in the striatum, and favor the notion that behavioral responses induced by low doses of apomorphine are mediated by presynaptic D-2 autoreceptors. (C) 1997 Wiley-Liss, Inc.