Effects of intrastriatal infusion of D2 receptor antisense oligonucleotide on apomorphine-induced behaviors in the rat.
An antisense oligonucleotide strategy was employed to specifically deplete postsynaptic striatal D2 receptors in order to determine the possible role of presynaptic D2 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 D2 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 micrograms/kg; subcutaneous) or low (50 micrograms/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 [3H]-raclopride binding, while binding of [3H]-SCH 23390 (D1 receptors) and [3H]-WIN 35428 (dopamine transporter) was unchanged. D2 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 D2 receptors in the striatum, and favor the notion that behavioral responses induced by low doses of apomorphine are mediated by presynaptic D2 autoreceptors.
Rajakumar
N
N
Department of Clinical Neurological Sciences, University of Western Ontario, London, Canada.
Laurier
L
L
Niznik
H B
HB
Stoessl
A J
AJ
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D002352:Carrier Proteins / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins; D017403:In Situ Hybridization; D007267:Injections; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D017072:Neostriatum / Q000502:physiology*; D009419:Nerve Tissue Proteins; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D013378:Substantia Nigra / Q000201:enzymology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D002352:Carrier Proteins; D018491:Dopamine Agonists; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D016376:Oligonucleotides, Antisense; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine