Effect of ebselen, a putative lithium mimetic, on central 5-HT2C receptor function in the mouse

I Antoniadou, D Buchmueller, P Walker, N Singh, S Vasudevan, GC Churchill, T Sharp. University of Oxford, Oxford, UK

Inhibition of inositol monophosphatase (IMPase) and decreased phosphoinositide (PI) signalling may underlie lithium’s antidepressant action (Berridge et al., 1989). Ebselen was recently identified through drug reprofiling as a potent IMPase inhibitor (Singh et al., 2009). The 5-HT2C receptor is Gq linked to the PI cycle and a mediator of antidepressant effects. Here we investigated the effect of ebselen on molecular and behavioural effects of the 5-HT2C receptor agonist Ro 60-0175 in mice.

For behavioural studies, mice (male C57BL/6, 20-25 g), were injected i.p. with vehicle or ebselen and 1 h later injected with Ro 60-0175. Locomotion was measured using activity meters. For molecular studies, mice were injected with vehicle or ebselen followed 1 h or 4h later by Ro 60-0175. Brains were removed 1 h after agonist injection. Regional brain abundance of mRNA of the activity-dependent genes c-fos and Arc was measured in frozen tissue sections by in situ hybridization using 35S-dATP labelled oligonucleotides. Autoradiograms were quantified by densitometry. Data were analysed statistically using one way ANOVA with post hoc LSD (n=6 per group). Mean ± SEM values are given.

Ro 60-0175 (2, 3 or 6 mg/kg) dose-dependently decreased locomotion. This effect was not blocked by ebselen (10 mg/kg). However ebselen decreased locomotion when injected alone. Ro 60-0175 (2, 3 or 6 mg/kg) dose-dependently increased c-fos and Arc mRNA in specific cortical areas, whereas ebselen alone (10 mg/kg) did not affect either gene. However, 1 h pretreatment with ebselen significantly (p<0.05) attenuated the increase in Arc mRNA induced by Ro 60-0175 (cingulate cortex vehicle 130±16, Ro 213±18, ebselen 167±17 nCi/g; somatosensory cortex vehicle 123±15, Ro 243±19, ebselen 181±13 nCi/g). Ebselen also reduced the Ro 60-0175-evoked increase in c-fos mRNA (somatosensory cortex vehicle 486± 55, Ro 667±64, ebselen 472± 41 nCi/g). Pretreatment with ebselen for 4 h also reduced Ro 60-0175 induced gene expression.

The current data indicate that ebselen attenuates central 5-HT2C receptor function in the mouse, as assessed by c-fos and Arc expression in cerebral cortex. This result is consistent with our previous finding that ebselen attenuates function of the 5-HT2A receptor (Antoniadou et al., 2011), which is also Gq coupled to the PI cycle. Together these findings support the hypothesis that ebselen attenuates 5-HT2 receptor function through IMPase inhibition and suggest that like lithium, the drug may have antidepressant properties.

This work was supported by the BBSRC, Greek state foundation and Onassis foundation.

Berridge, MJ, Downes, CP & Hanley, MR 1989, Neural and developmental actions of lithium: a unifying hypothesis. Cell, 59, 411-419.

Singh, N, Vasudevan, S, Thomas, J, et al 2010, Inositol monophosphatase: drug target or false alarm. European Neuropsychopharmacology, 20, pp.S166-S166

Antoniadou, I, Arsiwala, T, Serres, F, et al 2011, Effect of ebselen, a putative lithium-mimetic on central 5HT2A receptor function in the mouse. BPS meeting 2011