Ebselen has lithium-like effects on central 5-HT2A receptor function
| Autor: | T Arsiwala, T Fowler, Sridhar R. Vasudevan, Nisha Singh, I Antoniadou, Trevor Sharp, Grant C. Churchill, Elif Cadirci, Marianna Kouskou |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Pharmacology Agonist Arc (protein) Lithium (medication) biology Chemistry Ebselen medicine.drug_class Inositol monophosphatase Citalopram 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine medicine biology.protein Antidepressant Receptor 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | British Journal of Pharmacology. 175:2599-2610 |
| ISSN: | 0007-1188 |
| Popis: | Background and purpose Lithium'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-HT2A receptor, a Gq -protein coupled receptor involved in lithium's actions. Experimental approach 5-HT2A receptor 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-HT2A receptor agonists. Ebselen and lithium were administered either acutely or repeatedly prior to assessment of 5-HT2A receptor function. Because lithium and 5-HT2A receptor 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 results Acute and repeated administration of ebselen inhibited behavioural and IEG responses to the 5-HT2A receptor 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 implications Our data demonstrated lithium-mimetic effects of ebselen in different experimental models of 5-HT2A receptor 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. |
| Databáze: | OpenAIRE |
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