5-HT3 receptor activation is required for induction of striatal c-Fos and phosphorylation of ATF-1 by amphetamine
✍ Scribed by Lisa M. Genova; Steven E. Hyman
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 128 KB
- Volume
- 30
- Category
- Article
- ISSN
- 0887-4476
No coin nor oath required. For personal study only.
✦ Synopsis
Dopamine (DA) has been shown to be required for the induction of striatal gene expression by psychostimulants. However, direct DA agonists or selective inhibitors of DA reuptake are relatively weak inducers of striatal gene expression compared with cocaine or amphetamine. So although necessary, DA alone is not sufficient to mediate the full gene induction response to psychostimulants. In addition to its actions on the DA transporter, amphetamine also enhances serotonin (5-HT) release in the striatum. In this study, we investigated the mechanism by which 5-HT contributes to the regulation of striatal gene expression by amphetamine. We found that selective lesions of serotonergic terminals in the rat forebrain using 5,7-dihydroxytryptamine prevented the full induction of striatal c-Fos by 4 mg/kg amphetamine. Furthermore, amphetamineinduced striatal c-Fos was completely inhibited by administration of the 5-HT 3 receptor antagonist, MDL-72222, but not by the 5-HT 2A/2C receptor antagonist, ritanserin. Consistent with this finding, the induction of c-Fos by 5-HT in primary cultures of E18 striatal neurons devoid of DA input was blocked by the 5-HT 3 receptor antagonists, MDL-72222 and ICS 205-930, but not by 5-HT 2A/2C antagonism. Additionally, blockade of 5-HT 3 receptors by MDL-72222 inhibited the phosphorylation of activating transcription factor-1 (ATF-1) at Ser 63 by amphetamine, but not the phosphorylation of cAMP response element binding protein (CREB) at Ser 133 . These results suggest that 5-HT3 receptor activation may be required for amphetamine-induced expression of ATF-1-regulated target genes in the striatum, which may include c-Fos.