Abstract
Antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs) specifically increase serotonin (5-HT) levels in the synaptic cleft and are widely used to treat mood and anxiety disorders. There are 14 established subtypes of 5-HT receptors in rodents, each of which has regionally different expression patterns. Many preclinical studies have suggested that the hippocampus, which contains abundant 5-HT1A and 5-HT4 receptor subtypes in the dentate gyrus (DG), is critically involved in the mechanisms of action of antidepressants. This review article will analyze studies demonstrating regulation of hippocampal functions and hippocampus-dependent behaviors by SSRIs and similar serotonergic agents. Multiple studies indicate that 5-HT1A and 5-HT4 receptor signaling in the DG contributes to SSRI-mediated promotion of neurogenesis and increased neurotrophic factors expression. Chronic SSRI treatment causes functions and phenotypes of mature granule cells (GCs) to revert to immature-like phenotypes defined as a “dematured” state in the DG, and to increase monoamine reactivity at the dentate-to-CA3 synapses, via 5-HT4 receptor signaling. Behavioral studies demonstrate that the 5-HT1A receptors on mature GCs are critical for expression of antidepressant effects in the forced swim test and in novelty suppressed feeding; such studies also note that 5-HT4 receptors mediate neurogenesis-dependent antidepressant activity in, for example, novelty-suppressed feeding. Despite their limitations, the collective results of these studies describe a potential new mechanism of action, in which 5-HT1A and 5-HT4 receptor signaling, either independently or cooperatively, modulates the function of the hippocampal DG at multiple levels, any of which could play a critical role in the antidepressant actions of 5-HT-enhancing drugs.
Highlights
Serotonin (5-hydroxytryptamine, 5-HT) is a monoamine neurotransmitter that plays important roles in physiological and pathophysiological functions in the brain
Fluoxetine-induced facilitation in cell proliferation and early neural maturation in the dentate gyrus (DG) are attenuated in mice lacking granule cells (GCs)-specific 5-HT1A receptor, demonstrating that postsynaptic 5-HT1A signaling in GCs is involved in hippocampal neurogenesis induced by fluoxetine
It is possible that the alteration in maturation phenotypes in GCs following antidepressant treatment may restore cell function; that is, it may act as a ‘‘reset’’ button for GCs. 5-HT4 receptor activity contributes to fluoxetine-induced maturation phenotype changes in GCs in addition to facilitation of neurogenesis (Kobayashi et al, 2010)
Summary
Serotonin (5-hydroxytryptamine, 5-HT) is a monoamine neurotransmitter that plays important roles in physiological and pathophysiological functions in the brain. Fluoxetine-induced facilitation in cell proliferation and early neural maturation in the DG are attenuated in mice lacking GC-specific 5-HT1A receptor, demonstrating that postsynaptic 5-HT1A signaling in GCs is involved in hippocampal neurogenesis induced by fluoxetine.
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