Ventral tegmental area (VTA) injections of tyrosine hydroxylase phosphorothioate antisense oligonucleotide suppress operant behavior in rats.

Dopaminergic A 10 neurons are known to be the essential part of the brain reinforcement system. An antisense oligonucleotide corresponding to the start coding region of rat tyrosine hydroxylase (TH) mRNA, the transcriptional message of the rate limiting enzyme in the metabolic pathway leading to catecholamine synthesis, was constructed and injected into the ventral tegmental area (VTA). 36 h after injection operant behavior was markedly reduced, and this suppression was fully reversed within 5 days following the antisense injection. Accordingly, TH immunoreactivity in the VTA was reduced in comparison to control experiments using mixed bases oligonucleotides. Our results demonstrate that highly specific inhibition of TH expression can be accomplished in the intact mesolimbic system by antisense treatment, thus providing a novel tool for studies on motivational processes in vivo.