Serotonin decreases generation of dopaminergic neurons from mesencephalic precursors via serotonin type 7 and type 4 receptors

Inductive signals mediating the differentiation of neural precursors into serotonergic (5‐HT) or dopaminergic neurons have not been clarified. We have recently shown that in cell aggregates obtained from rat mesencephalic precursors, reduction of serotonin levels induces a marked increase in generation of dopaminergic neurons. In the present study we treated rat neurospheres with antagonists of the main subtypes of 5‐HT receptors, 5‐HT transport inhibitors, or 5‐HT receptor agonists, and studied the effects on generation of dopaminergic neurons. Cultures treated with Methiothepin (5‐HT 1,2,5,6,7 receptor antagonist), the 5‐HT 4 receptor antagonist GR113808;67:00–.or the 5‐HT 7 receptor antagonist SB 269970 showed a significant increase in generation of dopaminergic cells. Treatment with the 5‐HT 1B/1D antagonist GR 127935, the 5‐HT 2 antagonist Ritanserin, the 5‐HT transporter inhibitor Fluoxetine, the dopamine and norepinephrine transport inhibitor GBR 12935, or with both inhibitors together, or 5‐HT 4 or 5‐HT 7 receptor agonists induced significant decreases in generation of dopaminergic cells. Cultures treated with WAY100635 (5‐HT 1A receptor antagonist), the 5‐HT 3 receptor antagonist Ondasetron, or the 5‐HT 6 receptor antagonist SB 258585 did not show any significant changes. Therefore, 5‐HT 4 and 5‐HT 7 receptors are involved in the observed serotonin‐induced decrease in generation of dopaminergic neurons from proliferating neurospheres of mesencephalic precursors. 5‐HT 4 and 5‐HT 7 receptors were found in astrocytes and serotonergic cells using double immunolabeling and laser confocal microscopy, and the glial receptors appeared to play a major role. © 2006 Wiley Periodicals, Inc. J Neurobiol 67: 10–22, 2007