The authors have investigated the effects of a dopamine D3 receptor antisense oligodeoxynucleotide (ODN), on neuropeptides (neurotensin and dynorphin) and transcription factor (c-fos) mRNA levels in rat forebrain. 2. Intracerebroventricular injections of ODNs were made into the lateral ventricle (5 and 10 micrograms/h, for 5 days). Effect of antisense administration on dopamine D2 and D3 receptor binding were measured by means of receptor autoradiography. Neuropeptides and c-fos mRNA levels were evaluated by in situ hybridization using specific complementary RNA probes. 3. Dopamine D3 receptor densities were dose-dependently reduced in the shell of nucleus accumbens of rats that received the D3 antisense ODN. Sense and missense controls remained without effect. No significant effect was observed on D2 receptor binding in any of the ODN groups studied, as measured with [3H]raclopride binding. Concomitant reductions of dynorphin and neurotensin mRNA levels were observed in the shell of nucleus accumbens after D3 antisense ODN administration. Interestingly, the D3 antisense administration also reduced c-fos mRNA levels in the cingulate cortex of these animals. 4. The results show that D3 receptors may tonically regulate basal transcription factor, as well as neuropeptides, gene expression in the rat forebrain. These results clearly demonstrate that an antisense strategy could be useful to identify molecular targets under control of specific dopamine receptor subtypes.
