Ebselen has lithium-like effects on central 5-HT_2A receptor function

Area of Science:

• Neuropharmacology
• Molecular Biology
• Biochemistry

Background:

• Lithium's antidepressant effects are linked to inositol monophosphatase (IMPase) inhibition.
• Ebselen, an antioxidant, also inhibits IMPase.
• The 5-HT2A receptor, a Gq-protein coupled receptor, is implicated in lithium's actions.

Purpose of the Study:

• To investigate ebselen's effects on 5-HT2A receptor function.
• To compare ebselen's actions with lithium in relevant models.
• To explore ebselen's potential as an antidepressant augmenting agent.

Main Methods:

• Assessed 5-HT2A receptor function in mice via behavioral and molecular responses to agonists.
• Administered ebselen and lithium acutely and repeatedly.
• Tested ebselen's interaction with citalopram (SSRI) in microdialysis experiments.

Main Results:

• Ebselen and lithium inhibited 5-HT2A receptor-mediated behavioral and gene expression responses.
• Ebselen enhanced SSRI-induced serotonin release and increased brain serotonin synthesis.
• A selective IMPase inhibitor, but not a GSK inhibitor, mimicked ebselen's effect on DOI response.

Conclusions:

• Ebselen exhibits lithium-mimetic effects on 5-HT2A receptor function, likely via IMPase inhibition.
• These findings support clinical trials of ebselen for mood disorders.
• Ebselen may serve as an effective antidepressant augmenting agent.