Figure 1. 5-HT3 receptors are essential for exercise-induced increases in hippocampal neurogenesis and antidepressant effects.
(A) Exercise condition. (B) Exercise for 3 weeks increased BrdU-labeled mature granule cells (BrdU/NeuN double-labeled cells) in the hippocampal dentate gyrus in wild-type mice but not in Htr3a−/− mice. Scale bars, 50 μm. (C, D) Three weeks of exercise decreased immobility time, indicating antidepressant effects. By contrast, Htr3a−/− mice showed no decrease in immobility time after exercise for 3 weeks (C: forced swim test; D: tail suspension test). **p < 0.01; ***p < 0.001; ns, not significant. Means ± SEM are shown in all histograms. Modified with permission from ref. 27 and 36.

From: Molecular Mechanisms of Exercise-induced Hippocampal Neurogenesis and Antidepressant Effects

Figure 2. 5-HT3 receptor agonists produce increased hippocampal neurogenesis and antidepressant effects through a mechanism different from that of fluoxetine.
(A) Treatment of wild-type mice with a 5-HT3 receptor agonist (SR 57227A) produced antidepressant effects. (B) Treatment of wild-type and Htr3a−/− mice with fluoxetine (a commonly used SSRI) produced a dose-dependent antidepressant effect. Combination treatment of wild-type mice with fluoxetine (20 mg/kg) and SR 57227A (5 mg/kg) produced antidepressant effects that exceeded those produced by fluoxetine (20 mg/kg) alone. (C) Treatment of wild-type mice with SR 57227A for 3 days increased neural progenitor cells (BrdU/DCX double-labeled cells) in the hippocampal dentate gyrus. Treatment of wild-type and Htr3a−/− mice with fluoxetine for 3 weeks increased neural progenitor cells. Combined treatment of wild-type mice with fluoxetine and SR 57227A increased more neural progenitor cells than fluoxetine alone. Scale bars, 100 μm. SR, SR 57227A; Flx, fluoxetine; *p < 0.05; **p < 0.01; ***p < 0.001; ns, not significant. Means ± SEM are shown in all histograms. Modified with permission from ref. 29 and 36.

From: Molecular Mechanisms of Exercise-induced Hippocampal Neurogenesis and Antidepressant Effects

Figure 3. 5-HT3 receptor agonists promote IGF-1 release in the hippocampus and increase hippocampal neurogenesis.
(A) 5-HT3 receptors are highly expressed in neurons in the subgranular zone of the hippocampal dentate gyrus. (B) 5-HT3 receptors and IGF-1 are expressed in the same neurons in the hippocampal dentate gyrus. Arrowheads indicate neurons expressing both the 5-HT3 receptor and IGF-1. (C) The administration of SR 57227A to wild-type mice increased IGF-1 levels in the extracellular fluid of the hippocampus, but fluoxetine did not affect IGF-1 levels. An arrow indicates the administration time. (D) Treatment of wild-type mice with SR 57227A increased neural progenitor cells (BrdU/DCX double-labeled cells) in the hippocampal dentate gyrus, but this increase was blocked by the intrahippocampal administration of an IGF-1 receptor antagonist (AG 1024). 5-HT3R, 5-HT3 receptor; SR, SR 57227A; Flx, fluoxetine; Sal, saline; Veh, vehicle; AG, AG 1024; *p < 0.05; ns, not significant. Scale bars, 100 μm. Means ± SEM are shown in all histograms. Modified with permission from ref. 29, 31, and 36.

From: Molecular Mechanisms of Exercise-induced Hippocampal Neurogenesis and Antidepressant Effects

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