Central administration of dopamine D3 receptor antisense to rat:effects on locomotion, dopamine release and [H-3]spiperone binding

A 15-mer, all-phosphorothioate-modified antisense oligodeoxynucleotide (ASO) targeted against rat dopamine D3 receptor mRNA (4 mu M, 5 days) significantly reduced (28%) the amount of binding sites labelled with [H-3]spiperone in monolayer cultured Chinese hamster ovary (CHO) cells transfected with the complementary desoxy ribonucleic acid (cDNA) for the rat D3 receptor. In contrast, D3-ASO treatment did not reduce the amount of bound [H-3]spiperone in CHO cells transfected with D2 receptor cDNA. Intracerebroventricular infusion of D3-ASO (osmotic minipump, 10 mu g/mu l/h, 7 days) influenced dopamine receptor density in the limbic forebrain such that the upper part of the dopamine/[H-3] spiperone displacement curve tentatively representing the D3 receptor - was altered significantly. Spontaneous locomotor activity of non-habituated rats was increased significantly in D3-ASO-treated animals; in addition, in vivo microdialysis revealed a moderate increase in dopamine release in the nucleus accumbens in these animals. In all experiments, an oligodeoxynucleotide comprising the same nucleotides as the antisense sequence, but in random order, was used as control. It is concluded that the antisense strategy is useful for investigating the functional role of dopamine D3 receptors and that the dopamine D3 receptor is involved in rat locomotor behaviour.