Investigation of the neurochemical, molecular and behavioural properties of the putative lithium-mimetic, ebselen

Thesis

Lithium is the first choice drug for the treatment of bipolar disorder and it is also used as supplementary therapy for treatment-resistant depression. A leading candidate target of lithium is inositol monophosphatase (IMPase) which is critically involved in signalling via the phosphoinositide cycle (PI). Ebselen, first developed as an anti-inflammatory and anti-oxidant drug, has recently been shown to inhibit IMPase and therefore is a putative lithium-mimetic.

This project aimed to investigate the neuropharmacological effects of ebselen in mouse models relevant to depression. Initial studies examined the function of 5-HT_2A and 5-HT_2C receptors, which signal through PI cycle. Ebselen attenuated the responses of systemically administered 5-HT_2A agonists at the behavioural and molecular level; specifically the induction of head twitches and ear scratches and increased immediate early gene (IEG) expression. Lithium produced similar effects to ebselen in the same experiments. In addition, an IMPase inhibitor but not a GSK-3 inhibitor mimicked the effect of ebselen at the behavioural model of 5-HT_2A receptor function. Ebselen also reduced 5-HT_2C receptor function, as assessed using IEG expression, and lithium had a similar effect. Ebselen was also found to increase 5-HT synthesis in mouse brain regions as previously reported for lithium. In microdialysis studies, ebselen tended to enhance the increase in extracellular 5-HT levels induced by the SSRI citalopram in hippocampus. This finding was consistent with the observation that ebselen and citalopram increased IEG-expression when administered together but not when administered separately. Lastly, ebselen when administered repeatedly increased the abundance of a variety of gene markers of neuronal plasticity in mouse brain regions. Lithium also increased the abundance of markers of neuronal plasticity.

Overall, the present study found that ebselen attenuated 5-HT₂ receptor function and partially augmented the effects of citalopram, while it increased markers of neuronal plasticity. These effects of ebselen were largely mimicked by lithium. These findings show that ebselen has similar neuropharmacological effects to lithium across a range of mouse models relevant to depression. The antidepressant potential of ebselen is discussed.

Authors: Antoniadou, I

• DOI: 10.5287/ora-a4xo6peod
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford