Journal
BIOLOGICAL PSYCHIATRY
Volume 61, Issue 1, Pages 65-69Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.biopsych.2006.03.020
Keywords
amphetamine; dopamine transporter; knockout mice; tyrosine hydroxylase; dopamine; RNA interference
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Funding
- NIDA NIH HHS [DA-13511] Funding Source: Medline
- NATIONAL INSTITUTE ON DRUG ABUSE [R01DA013511] Funding Source: NIH RePORTER
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Background: Recent reports have suggested effectiveness of RNA interference (RNAi) for the analysis of gene,functions in the brain. This study sought to determine the efficiency of local small interfering RNA (siRNA) injections, comparing this approach with animals generated through classical gene targeting. Methods: Small interfering RATA against dopamine transporter (DAT) (35 mu g/14 days) or tyrosine hydroxylase (TH) (15 mu g/3 days) was injected into the ventral tegmental/substantia nigra areas of the brain of adult wildtype or DA T-knockout mice, respectively. Results: Local injections of siRNA resulted in a 35% to 40% reduction of DAT and TH protein levels in the striatum, respectively. Despite negligible effect of DAT knockdown on novelty-induced locomotion, the locomotor response of DAT siRIVA treated animals to amphetamine was blunted similar to what is observed in the DA T heterozygote animals. Since incomplete reduction of TH levels in normal mice does not produce behavioral effects, TH siRNA experiments were carried out in DAT-knockout animals that show increased dependence on newly synthesized dopamine. Knockdown of TH in these animals resulted in reduced basal locomotion. Conclusions: Local injection of siRIVA in the brain reduced gene expression by 40016 to 50%, suggesting that siRNA-mediated knockdown of genes in the brain can be a complementary tool to classical transgenesis for the analysis of gene functions.
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