A novel butyrylcholinesterase inhibitor induces antidepressant, pro-cognitive, and anti-anhedonic effects in Flinders Sensitive Line rats : the role of the ghrelin-dopamine cascade

Olivier, Nadia (author), Harvey, Brian H. (author), Gobec, Stanislav (author), Mohammed, Shahid (author), Košak, Urban (author), Žakelj, Simon (author), Brink, Christiaan B. (author)

Background and purpose: Major depressive disorder (MDD) is often treatment resistant, particularly in addressing anhedonia and cognitive deficits. Novel pharmacological strategies are needed. While butyrylcholinesterase, ghrelin, and dopamine (DA) have been well studied in the context of stress and MDD, their interaction remains unclear. Experimental approach: The dose-dependent antidepressant effects of a novel butyrylcholinesterase inhibitor (BChEI) were evaluated in the Flinders Sensitive Line (FSL) rat model of MDD. Behavioural assessments included the forced swim test (despair), sucrose preference test (reward-related), and novel object recognition test (cognition). Brain-derived neurotrophic factor (BDNF), acetylcholine (ACh), and brain monoamines were analysed, as well as serum growth hormone and acyl- and desacyl-ghrelin. To confirm the role of ghrelin, pharmacological exploration was undertaken using the ghrelin receptor antagonist, D-Lys-3-GHRP-6. Key results: FSL rats had significantly lower ghrelin ratios, BDNF, ACh, DA and growth hormone levels. In FSL rats, both BChEI and escitalopram significantly reduced despair. BChEI significantly outperformed escitalopram in enhancing reward-related and cognitive behaviours. Biochemically, BChEI treatment significantly increased ghrelin ratios and brain DA levels without altering brain 5-HT, ACh or BDNF. D-Lys-3-GHRP-6 significantly reversed the antidepressant-like, rewarding, and pro-cognitive effects of BChEI, accompanied by significant reductions in BDNF and DA. Conclusions and implications: FSL rats display impaired ghrelin, DA, serotonin, growth hormone, and BDNF signalling, akin to MDD. BChEI exerts antidepressant-like effects across despair, reward, and cognitive domains, most likely via the BChE-ghrelin-DA cascade. Reversal of these effects by ghrelin antagonism underscores the critical role of ghrelin, specifically via growth hormone secretagogue receptor-ghrelin interaction. These findings suggest a potentially novel multimodal neurobiological target for the treatment of MDD.

• Language: English
• Keywords: depression, butyrylcholinesterase inhibitor, GhrelinD, Lys-3-GHRP-6, dopamine, cognition, anhedonia, reward
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2025
• Number of pages: Str. 1-15
• Numbering: Vol. 187, art. 118093
• PID: 20.500.12556/RUL-171954
• UDC: 615.015:616.895.4
• ISSN on article: 0753-3322
• DOI: 10.1016/j.biopha.2025.118093
• COBISS.SI-ID: 246717955
• Publication date in RUL: 04.09.2025

Record is a part of a journal

• Title: Biomedicine & pharmacotherapy
• Shortened title: Biomed. pharmacother.
• Publisher: Elsevier Masson
• ISSN: 0753-3322
• COBISS.SI-ID: 25098240

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: depresija, zaviralec butirilholinesteraze, GhrelinD, Lys-3-GHRP-6, dopamin, kognitivne sposobnosti, anhedonija, nagrada, farmakologija, depresija (medicina)