13-<i>cis</i>-Retinoic Acid Alters Intracellular Serotonin, Increases 5-HT_1AReceptor, and Serotonin Reuptake Transporter Levels<i>In Vitro</i>

Abstract

In addition to their established role in nervous system development, vitamin A and related retinoids are emerging as regulators of adult brain function. Accutane (13-cis-retinoic acid, isotretinoin) treatment has been reported to increase depression in humans. Recently, we showed that chronic administration of 13-cis-retinoic acid (13-cis-RA) to adolescent male mice increased depression-related behaviors. Here, we have examined whether 13-cis-RA regulates components involved in serotonergic neurotransmission in vitro. We used the RN46A-B14 cell line, derived from rat embryonic raphe nuclei. This cell line synthesizes serotonin (5-hydroxytryptamine, 5-HT) and expresses the 5-HT(1A) receptor and the serotonin reuptake transporter (SERT). Cells were treated with 0, 2.5, or 10 microM 13-cis-RA for 48 or 96 hrs, and the levels of 5-HT; its metabolite, 5-hydroxyindoleacetic acid (5HIAA); 5-HT(1A) receptor; and SERT were determined. Treatment with 13-cis-RA for 96 hrs increased the intracellular levels of 5-HT and tended to increase intra-cellular 5HIAA levels. Furthermore, 48 hrs of treatment with 2.5 and 10 microM 13-cis-RA significantly increased 5-HT(1A) protein to 168.5 +/- 20.0% and 148.7 +/- 2.2% of control respectively. SERT protein levels were significantly increased to 142.5 +/- 11.1% and 119.2 +/- 3.6% of control by 48 hrs of treatment with 2.5 and 10 microM of 13-cis-RA respectively. Increases in both 5-HT(1A) receptor and SERT proteins may lead to decreased serotonin availability at synapses. Such an effect of 13-cis-RA could contribute to the increased depression-related behaviors we have shown in mice.