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Fluoxetine, not donepezil, reverses anhedonia, cognitive dysfunctions and hippocampal proteome changes during
M G Gottschalk1, P Mortas2, M Haman2
1Cambridge Centre for Neuropsychiatric Research, Department of Chemical Engineering and Biotechnology, University of Cambridge, UK.
Abstract:
While anhedonia is considered a core symptom of major depressive disorder (MDD), less attention has been paid to cognitive dysfunctions. We evaluated the behavioural and molecular effects of a selective serotonin re-uptake inhibitor (SSRI, fluoxetine) and an acetylcholinesterase inhibitor (AChEI, donepezil) on emotional-cognitive endophenotypes of depression and the hippocampal proteome. A chronic social defeat (SD) procedure was followed up by "reminder" sessions of direct and indirect SD. Anhedonia-related behaviour was assessed longitudinally by intracranial self-stimulation (ICSS). Cognitive dysfunction was analysed by an object recognition test (ORT) and extinction of fear memory. Tandem mass spectrometry (MSE) and protein-protein-interaction (PPI) network modelling were used to characterise the underlying biological processes of SD and SSRI/AChEI treatment. Independent selected reaction monitoring (SRM) was conducted for molecular validation. Repeated SD resulted in a stable increase of anhedonia-like behaviour as measured by ICSS. Fluoxetine treatment reversed this phenotype, whereas donepezil showed no effect. Fluoxetine improved recognition memory and inhibitory learning in a stressor-related context, whereas donepezil only improved fear extinction. MSE and PPI network analysis highlighted functional SD stress-related hippocampal proteome changes including reduced glutamatergic neurotransmission and learning processes, which were reversed by fluoxetine, but not by donepezil. SRM validation of molecular key players involved in these pathways confirmed the hypothesis that fluoxetine acts via increased AMPA receptor signalling and Ca2+-mediated neuroplasticity in the amelioration of stress-impaired reward processing and memory consolidation. Our study highlights molecular mediators of SD stress reversed by SSRI treatment, identifying potential viable future targets to improve cognitive dysfunctions in MDD patients.
Insights
Selective serotonin re-uptake inhibitors (SSRIs) like fluoxetine effectively treat anhedonia and cognitive dysfunction in major depressive disorder (MDD) by restoring hippocampal proteome changes. Acetylcholinesterase inhibitors (AChEIs) showed limited efficacy in this study.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Anhedonia and cognitive dysfunction are key symptoms of major depressive disorder (MDD).
- The molecular mechanisms underlying these symptoms and the effects of treatments like SSRIs and AChEIs on the hippocampus are not fully understood.
Purpose of the Study:
- To investigate the behavioral and molecular effects of fluoxetine (SSRI) and donepezil (AChEI) on depression-related emotional and cognitive deficits.
- To identify hippocampal proteome changes associated with chronic social defeat (SD) stress and their modulation by fluoxetine and donepezil.
Main Methods:
- Chronic social defeat (SD) model in rodents to induce depression-like phenotypes.
- Behavioral assessments including intracranial self-stimulation (ICSS), object recognition test (ORT), and fear memory extinction.
- Proteomic analysis using tandem mass spectrometry (MS^E) and protein-protein interaction (PPI) network modeling.
- Molecular validation through selected reaction monitoring (SRM).
Main Results:
- Chronic SD induced anhedonia-like behavior and cognitive deficits.
- Fluoxetine reversed anhedonia, improved recognition memory, and inhibitory learning.
- Donepezil showed no effect on anhedonia but improved fear extinction.
- Proteomic analysis revealed SD-induced changes in hippocampal glutamatergic neurotransmission and learning pathways, reversed by fluoxetine.
Conclusions:
- Fluoxetine effectively ameliorates anhedonia and cognitive dysfunction in a depression model by modulating hippocampal proteome, particularly AMPA receptor signaling and neuroplasticity.
- Donepezil demonstrated limited therapeutic effects on the evaluated emotional-cognitive endophenotypes.
- This study identifies potential molecular targets for treating cognitive deficits in MDD.
