D2 Dopamine Antisense RNA Expression Vector, Unlike Haloperidol, Produces Long-term Inhibition of D2Dopamine-Mediated Behaviors without Causing Up-regulation of D2 Dopamine Receptors

• Published in: The Journal of pharmacology and experimental therapeutics 1998-06, Vol.285 (3), p.1187
• Main Authors: Genoveva Davidkova, Long-Wu Zhou, Mark Morabito, Sui-Po Zhang, Benjamin Weiss
• Format: Article
• Language: English
• ISSN: 0022-3565; 1521-0103

Long-term inhibition of D 2 dopamine receptors using classic D 2 dopamine receptor antagonists such as haloperidol often causes a compensatory up-regulation of the D 2 dopamine receptors. We investigated whether the long-term inhibition of D 2 dopamine receptors using an eukaryotic expression vector housing a cDNA sequence encoding an antisense RNA directed to the D 2 dopamine receptor transcript (D 2 antisense vector) would also produce up-regulation of the D 2 receptors. Single, bilateral injections of the D 2 antisense vector into the corpora striata of mice inhibited the stereotypy induced by acute challenge injections with the D 2 /D 3 dopamine receptor agonist quinpirole but did not inhibit the grooming induced by acute challenge injections with the D 1 agonist SKF 38393. Similar treatment with the D 2 antisense vector produced a long-term (>1 month) cataleptic response without producing tolerance to challenge injections with haloperidol. By contrast, catalepsy induced by a single injection of haloperidol lasted only ∼2 days, and tolerance developed to its effects after long-term treatment. Repeated treatment of mice with haloperidol resulted in an inhibition of apomorphine-induced climbing behavior throughout the time of treatment with haloperidol, but the climbing behavior markedly increased to levels significantly higher than that of the control mice immediately after withdrawal from haloperidol treatment. This increased climbing was accompanied by increased levels of D 2 dopamine receptors in the striatum. By contrast, single, bilateral intrastriatal injections of the D 2 antisense vector significantly inhibited apomorphine-induced climbing for ∼30 days but failed to increase the climbing behavior or the levels of D 2 dopamine receptors in striatum over those of the control values. These results suggest that a single injection of a D 2 antisense RNA expression vector into mouse striatum produces specific, long-term inhibition of D 2 dopamine receptor behaviors without causing a compensatory increase in the levels or function of D 2 dopamine receptors.