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

Abstract

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, 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 serotonininduced 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. '

Neuron-glia interaction through Serotonin-BDNF-NGFR axis enables regenerative neurogenesis in Alzheimer’s model of adult zebrafish brain

“…Although depletion of serotonin reduces adult neurogenic outcome in rats [56], elevated levels of serotonin in serotonin transporter (SERT)-deficient mice did not affect NSC proliferation and neurogenesis [57,58]. In mesencephalic and hippocampal progenitors of mouse brain, inhibition of serotonin receptors or knocking out serotonin-producing enzymes to generate hyposerotonergic phenotypes had positive effects on neurogenesis [59][60][61][62] ascertaining a negative role for serotonin on NSC plasticity. These findings indicate that the effects of serotonin on NSCs are context dependent and may run through intermediary secondary signaling mechanisms, which supports our findings.…”

Obesity is associated with high serotonin 4 receptor availability in the brain reward circuitry

“…The receptor has been found to influence cognitive functions and affective symptoms and interestingly, studies have shown that the 5-HT 4 R seems to exert control over dopamine transmission (Parga et al, 2007;Porras et al, 2002). Animal studies have identified the 5-HT 2C , 5-HT 1B , and 5-HT 6 receptors as influencing food intake and these receptors are considered as pharmacological anti-obesity targets (Garfield and Heisler, 2009).…”

<p>Serotonin Type 6 and 7 Receptors as a Novel Therapeutic Target for the Treatment of Schizophrenia</p>

“…This is confirmed by an increase in generation of dopamine neurons after elimination of the 5-HT neurons or reduction of 5-HT levels using methiothepin (5-HT1,2,5,6,7 receptor antagonist), and the 5-HT7Rs antagonist SB 269,970. 52 …”