ACTIVATION OF TRANSCRIPTION FACTOR GENES IN STRIATUM BY COCAINE - ROLE OF BOTH SEROTONIN AND DOPAMINE SYSTEMS

Acute administration of cocaine increases expression of the transcript ion factor genes c-fos and zif268 in the striatum. This response is th ought to be mediated via D1 dopamine (DA) receptors, as it is blocked by the selective D1 receptor antagonist SCH 23390. However, the direct ly acting D1 receptor agonists, apomorphine and SKF 38393, do not mimi c cocaine's activation of these genes raising the possibility that D1 receptor activation is necessary, but not sufficient, to trigger trans cription factor expression. Because cocaine blocks uptake of norepinep hrine (NE) and serotonin (5-HT), as well as DA, we examined whether co caine's ability to inhibit NE and 5-HT uptake may contribute to its in duction of c-fos and zif268 expression in striatum. In examining the e ffects of selective monoamine uptake inhibitors, we observed that fluo xetine or citalopram, selective inhibitors of 5-HT uptake, potentiated the ability of mazindol, a DA and NE uptake inhibitor, to induce zif2 68 and c-fos expression, even though these 5-HT uptake inhibitors had no effect when administered alone. In contrast, the selective NE uptak e inhibitor, desipramine, administered alone, or in combination with f luoxetine, did not increase expression of zif268 or c-fos. Furthermore , selective denervation of 5-HT projections by p-chloroamphetamine tre atment attenuated the increase in zif268 and c-fos expression induced by cocaine in the striatum. In contrast, selective lesions of NE proje ctions with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride failed to block cocaine's activation of these genes in the striatum. Taken together, these findings indicate that cocaine's ability to indu ce striatal expression of c-fos and zif268 is mediated by its effects on both the 5-HT and DA systems.