Dopamine D3 receptor antisense administration reduces basal c-fos and NGFI-B mRNA levels in the rat forebrain.

The physiological role of the dopamine D3 receptor is still unclear. The absence of selective pharmacological tools that can discriminate D3 over D2 receptor subtype activity is a major drawback in the elucidation of D3-mediated functions. In order to study D3 receptor actions in rat brain, we have developed an antisense strategy, using oligodeoxynucleotide (ODN) directed against the mRNA of the D3 receptor. Dopamine D2-like agents induce a cascade of events that affect numerous genes in the CNS. Transcription factors are among the most dramatically affected. Using the antisense strategy, we explored the involvement of the D3 receptor on the expression of two classes of transcription factors, the c-fos and NGFI-B. Intracerebroventricular injections of ODNs were made into the lateral ventricle (8 microg/hour, for 5 days). The effect of antisense administration on dopamine D1, D2, and D3 receptor binding was measured by means of receptor autoradiography, whereas transcription factor mRNA levels (c-fos and NGFI-B) were evaluated by in situ hybridization using specific complementary RNA probes. Dopamine D3 receptor levels were significantly decreased in the shell of nucleus accumbens of rats that received the D3 antisense ODN, whereas dopamine D1 and D2 receptor levels were not affected. Basal c-fos mRNA levels were concomitantly reduced in both cingulate and medial prefrontal cortices. Basal NGFI-B mRNA levels were also reduced in the cingulate cortex, shell of nucleus accumbens, and in the dorsomedial striatum, whereas the core of nucleus accumbens and the dorsolateral striatum were not affected after D3 antisense ODN treatments. Our results suggest that D3 receptors may tonically regulate transcription factor expression in rat forebrain. This supports the hypothesis of a constitutive activity of the D3 receptor in vivo.