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Ebselen has lithium-like effects on central 5-HT2A receptor function.
Antoniadou, I; Kouskou, M; Arsiwala, T; Singh, N; Vasudevan, S R; Fowler, T; Cadirci, E; Churchill, G C; Sharp, T.
Afiliação
  • Antoniadou I; Department of Pharmacology, University of Oxford, Oxford, UK.
  • Kouskou M; Department of Pharmacy, European University of Cyprus, Nicosia, Cyprus.
  • Arsiwala T; Department of Pharmacology, University of Oxford, Oxford, UK.
  • Singh N; Department of Pharmacology, University of Oxford, Oxford, UK.
  • Vasudevan SR; Department of Pharmacology, University of Oxford, Oxford, UK.
  • Fowler T; Department of Pharmacology, University of Oxford, Oxford, UK.
  • Cadirci E; Department of Pharmacology, University of Oxford, Oxford, UK.
  • Churchill GC; Department of Pharmacology, University of Oxford, Oxford, UK.
  • Sharp T; Department of Pharmacology, University of Oxford, Oxford, UK.
Br J Pharmacol ; 175(13): 2599-2610, 2018 07.
Article em En | MEDLINE | ID: mdl-29488218
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Azóis / Compostos Organosselênicos / Receptor 5-HT2A de Serotonina / Lítio / Antioxidantes Limite: Animals Idioma: En Revista: Br J Pharmacol Ano de publicação: 2018 Tipo de documento: Article País de publicação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Azóis / Compostos Organosselênicos / Receptor 5-HT2A de Serotonina / Lítio / Antioxidantes Limite: Animals Idioma: En Revista: Br J Pharmacol Ano de publicação: 2018 Tipo de documento: Article País de publicação: Reino Unido