Dataset Information

Chronic Treatment with the 5-HT1A Receptor Partial Agonist Tandospirone Increases Hippocampal Neurogenesis.

ABSTRACT:

Introduction

A large-scale clinical trial, the Sequence Trial Alternatives to Relieve Depression (STAR*D) study, concluded that about one-third of the studied patients with major depressive disorder remitted during the initial treatment with selective serotonin reuptake inhibitors and that approximately half of the remitted subjects relapsed over a 1-year follow-up. The development of new therapeutic approaches with potent efficacy and good tolerability for the treatment of depressive disorders is of great importance. Adult hippocampal neurogenesis has been proposed to be important for understanding and treating depression and anxiety. The present study aimed to elucidate whether or not 5-hydroxytryptamine 1A (5-HT1A) receptor partial agonists have a potential therapeutic effect for the treatment of depressive and anxiety disorders, from the standpoint of neurogenesis.

Methods

Male Sprague-Dawley rats were subcutaneously administered a vehicle or tandospirone (TDS) (1 or 10 mg/kg) once daily for 14 days. The effects of chronic TDS treatment on neurogenesis were evaluated on the day after the last injection. The quantification of hippocampal neurogenesis was estimated using immunostaining with doublecortin (DCX), a marker protein of newborn neurons.

Results

Chronic TDS treatment resulted in a significant increase in the number of DCX-positive cells per volume of dentate gyrus in a dose-dependent manner.

Conclusion

The results strongly suggest that 5-HT1A receptor partial agonists would be useful and beneficial in the treatment of depressive and anxiety disorders through increased hippocampal neurogenesis.

SUBMITTER: Mori M

PROVIDER: S-EPMC4381917 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Serotonin receptors are potential neuroprotective agents in degenerative diseases of the central nervous system. The protective effects of serotonin receptor (5-HT1A) agonists on the survival and function of retinal ganglion cells (RGCs) by regulating the release of the presynaptic neurotransmitter γ-aminobutyric acid (GABA) were confirmed in our previous study of a chronic glaucoma rat model. However, the roles of excitatory amino acids and their interactions with the 5-HT1A receptor in glaucoma remain unknown. Here, we found that ocular hypertension increased glutamine synthetase (GS) and excitatory amino acid transporter 2 (EAAT2) expression in rat retinas. In addition, the high expression of GS and EAAT2 induced by glaucoma was downregulated by the 5-HT1A receptor agonist 8-OH-DPAT and the 5-HT1A receptor antagonist WAY-100635, respectively. Patch-clamp techniques were used to record glutamate receptor-mediated spontaneous and miniature glutamatergic excitatory post-synaptic currents (sEPSCs and mEPSCs) as well as L-glutamate-induced current in OFF-type and ON-type RGCs in rat retinal slices. Although there were no significant differences in the frequency and amplitude of sEPSC and mEPSC release between normal and glaucoma OFF- and ON-type RGCs, exogenous 8-OH-DPAT administration specifically reduced the frequency, but not the amplitude, of sEPSC and mEPSC release in glaucoma OFF-type rather than ON-type RGCs; these effects were completely blocked by WAY-100635. In summary, 8-OH-DPAT decreases and increases GS and EAAT2 expression of glaucomatous retina, respectively, while decreasing sEPSC and mEPSC frequency. In contrast, WAY-100635 increases and decreases GS and EAAT2 expression of glaucomatous retina, respectively, while increasing sEPSC and mEPSC frequency. The reduction of glutamatergic presynaptic transmission by 8-OH-DPAT deactivates RGCs at the neural network level and reduces the excitotoxic damage in the pathological process of chronic glaucoma.