Dopamine D-3 receptor antisense administration reduces basal c-fos and NGFI-B mRNA levels in the rat forebrain

The physiological role of the dopamine D-3 receptor is still unclear. The a bsence of selective pharmacological tools that can discriminate D-3 over D- 2 receptor subtype activity is a major drawback in the elucidation of D-3-m ediated functions. In order to study D-3 receptor actions in rat brain, we have developed an antisense strategy using oligodeoxynucleotide (ODN) direc ted against the mRNA of the D-3 receptor. Dopamine D-2-like agents induce a cascade of events that affect numerous genes in the CNS. Transcription fac tors are among the most dramatically affected. Using the antisense strategy , we explored the involvement of the D-3 receptor on the expression of two das ses of transcription factors, the c-fos and NGFI-B. Intracerebroventric ular injections of ODNs were made into the lateral ventricle (8 mu g/hour, for 5 days). The effect of antisense administration on dopamine D-1, D-2, a nd D-3 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 D-3 receptor levels were significantly decreased in the shell of nucleus ac cumbens of rats that received the D-3 antisense ODN, whereas dopamine D-1 a nd D-2 receptor levels were not affected. Basal c-fos mRNA levels were conc omitantly reduced in both cingulate and medial prefrontal cortices. Basal N GFI-B mRNA levels were also reduced in the cingulate cortex, shell of nucle us accumbens, and in the dorsomedial striatum, whereas the core of nucleus accumbens and the dorsolateral striatum were not affected after D-3 antisen se ODN treatments. Our results suggest that D-3 receptors may tonically reg ulate transcription factor expression in rat forebrain. This supports the h ypothesis of a constitutive activity of the D-3 receptor in vivo. Synapse 3 2:51-57, 1999, (C) 1999 Wiley-Liss, Inc.