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BACKGROUND AND PURPOSE: Lithium's antidepressant action may be mediated by inhibition of inositol monophosphatase (IMPase), a key enzyme in Gqprotein coupled receptor signalling. Recently, the antioxidant agent ebselen was identified as an IMPase inhibitor. Here we investigated both ebselen and lithium in models of the 5-HT2Areceptor, a Gqprotein coupled receptor implicated in lithium's actions. EXPERIMENTAL APPROACH: 5-HT2Areceptor function was modelled in mice by measuring the behavioural (head-twitches) and cortical immediate early gene (IEG; Arc, c-fos and Erg2 mRNA) responses to 5-HT2Areceptor agonist administration. Ebselen and lithium were administered either acutely or chronically prior to assessment of 5-HT2Areceptor function. Given the SSRI augmenting action of lithium and 5-HT2Aantagonists, ebselen was also tested for this action by co-administration with the SSRI citalopram in microdialysis (extracellular 5-HT) experiments. KEY RESULTS: Acute and repeated administration of ebselen inhibited behavioural and IEG responses to the 5-HT2Areceptor agonist DOI. Repeated lithium also inhibited DOI-evoked behavioural and IEG responses. In comparison, a selective IMPase inhibitor (L-690,330) attenuated the behavioural response to DOI whereas glycogen synthase kinase inhibitor (AR-A014418) did not. Finally, ebselen increased regional brain 5-HT synthesis and enhanced the increase in extracellular 5-HT induced by citalopram. CONCLUSIONS AND IMPLICATIONS: The current data demonstrate lithium-mimetic effects of ebselen in different experimental models of 5-HT2Areceptor function, likely mediated by IMPase inhibition. This evidence of lithium-like neuropharmacological effects of ebselen adds further support for the clinical testing of ebselen in mood disorder, including as an antidepressant augmenting agent.

Original publication

DOI

10.1111/bph.14179

Type

Journal article

Journal

Br J Pharmacol

Publication Date

27/02/2018

Keywords

5-HT2A, IMPase, ebselen, hallucinogen, lithium, mood disorder