Serotonin-Induced Increases in Adult Cell Proliferation and Neurogenesis are Mediated Through Different and Common 5-HT Receptor Subtypes in the Dentate Gyrus and the Subventricular Zone

Abstract

Increase in serotonin (5-HT) transmission has profound antidepressant effects and has been associated with an increase in adult neurogenesis. The present study was aimed at screening the 5-HT receptor subtypes involved in the regulation of cell proliferation in the subgranular layer (SGL) of the dentate gyrus (DG) and the subventricular zone (SVZ) and to determine the long-term changes in adult neurogenesis. The 5-HT1A, 5-HT1B, and 5-HT2 receptor subtypes were chosen for their implication in depression and their location in/ or next to these regions. Using systemic administration of various agonists and antagonists, we show that the activation of 5-HT1A heteroreceptors produces similar increases in the number of bromodeoxyuridine-labeled cells in the SGL and the SVZ (about 50% over control), whereas 5-HT2A and 5-HT2C receptor subtypes are selectively involved in the regulation of cell proliferation in each of these regions. The activation of 5-HT2C receptors, largely expressed by the choroid plexus, produces a 56% increase in the SVZ, while blockade of 5-HT2A receptors produces a 63% decrease in the number of proliferating cells in the SGL. In addition to the influence of 5-HT1B autoreceptors on 5-HT terminals in the hippocampus and ventricles, 5-HT1B heteroreceptors also regulate cell proliferation in the SGL. These data indicate that multiple receptor subtypes mediate the potent, partly selective of each neurogenic zone, stimulatory action of 5-HT on adult brain cell proliferation. Furthermore, both acute and chronic administration of selective 5-HT1A and 5-HT2C receptor agonists produce consistent increases in the number of newly formed neurons in the DG and/or olfactory bulb, underscoring the beneficial effects of 5-HT on adult neurogenesis.

High dose of 8-OH-DPAT decreases maximal dentate gyrus activation and facilitates granular cell plasticity in vivo

“…Indeed, recent imaging studies have shown a reduced serotonin 5-Ht 1A R binding in temporal cortex and hippocampus of tLE patients (Giovacchini et al 2005) that is correlated with scores on depression scales (theodore et al 2007) and memory impairment (theodore et al 2012). these findings are in agreement with the evidence that 5-Ht 1A hypofunction induces hippocampal hyperexcitability (Chugani and Chugani 2003), reduces neoneurogenesis (Banasr et al 2004) and hippocampal functional integrity (Chugani and Chugani 2003) and impairs memory processes (Ogren et al 2008).…”

Mechanisms Contributing to the Phase-Dependent Regulation of Neurogenesis by the Novel Antidepressant, Agomelatine, in the Adult Rat Hippocampus

“…We also compared the regional influence of agomelatine with the effects of melatonin and those of the selective 5-HT 2C receptors antagonists, SB242,084, SB243,213, and S32006, upon hippocampal cell proliferation (bromodeoxyuridine (BrdU) injected the day after the last drug administration) and survival (BrdU injected before the first drug administration). Indeed, we have previously shown that various 5-HT receptor subtypes are involved in the regulation of adult neurogenesis and 5-HT 2C receptors have a selective influence depending on the neurogenic zones (Banasr et al, 2004). Here, we further specified the agomelatine's action on cell survival by examining the effect of a pretreatment with a melatonin receptor antagonist (S22153).…”

Serotonin Depletion Hampers Survival and Proliferation in Neurospheres Derived from Adult Neural Stem Cells

“…Chronic treatment with serotonergic antidepressants correlates with neurogenesis in the adult hippocampus. The production of new neurons may be required for the behavioral effects of these moleculesFit may also indicate that progenitor survival, proliferation, and differentiation are modulated by serotonergic neurotransmission (Banasr et al, 2004;Daszuta, 1999, 2000a, b;Jacobs et al, 2000;Santarelli et al, 2003).…”