Ebselen has lithium‐like effects on central5‐HT2Areceptor function

Background and PurposeLithium's antidepressant action may be mediated by inhibition of inositol monophosphatase (IMPase), a key enzyme in Gq‐protein 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 Gq‐protein coupled receptor involved in lithium's actions.Experimental Approach5‐HT2Areceptor function was assessed in mice by measuring the behavioural (head‐twitches, ear scratches) and molecular (cortical immediate early gene [IEG] mRNA; Arc, c‐fos, Egr2) responses to 5‐HT2Areceptor agonists. Ebselen and lithium were administered either acutely or repeatedly prior to assessment of 5‐HT2Areceptor function. Because lithium and 5‐HT2Areceptor antagonists augment the action of selective serotonin reuptake inhibitors (SSRIs), ebselen was tested for this activity by co‐administration with the SSRI citalopram in microdialysis (extracellular 5‐HT) experiments.Key ResultsAcute 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‐690330) attenuated the behavioural response to DOI whereas glycogen synthase kinase inhibitor (AR‐A014418) did not. Finally, ebselen enhanced the increase in extracellular 5‐HT induced by citalopram, and also increased regional brain 5‐HT synthesis.Conclusions and ImplicationsOur data demonstrated lithium‐mimetic effects of ebselen in different experimental models of 5‐HT2Areceptor function, probably mediated by IMPase inhibition. This evidence of lithium‐like neuropharmacological effects of ebselen adds further support for the clinical testing of ebselen in mood disorders, including as an antidepressant augmenting agent.