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The Unpredictable Chronic Mild Stress Protocol for Inducing Anhedonia in Mice
Published on: October 24, 2018
Chronic 5-HT4 receptor agonist treatment restores learning and memory deficits in a neuroendocrine mouse model of
Flavie Darcet1, Alain M Gardier1, Denis J David1
1Université Paris-Saclay, Univ. Paris-Sud, Faculté de Pharmacie, CESP, INSERM UMRS1178, Chatenay-Malabry 92296, France.
Abstract:
Cognitive disturbances are often reported as serious invalidating symptoms in patients suffering from major depression disorders (MDD) and are not fully corrected by classical monoaminergic antidepressant drugs. If the role of 5-HT4 receptor agonists as cognitive enhancers is well established in naïve animals or in animal models of cognitive impairment, their cognitive effects in the context of stress need to be examined. Using a mouse model of anxiety/depression (CORT model), we reported that a chronic 5-HT4 agonist treatment (RS67333, 1.5mg/kg/day) restored chronic corticosterone-induced cognitive deficits, including episodic-like, associative and spatial learning and memory impairments. On the contrary, a chronic monoaminergic antidepressant drug treatment with fluoxetine (18mg/kg/day) only partially restored spatial learning and memory deficits and had no effect in the associative/contextual task. These results suggest differential mechanisms underlying cognitive effects of these drugs. Finally, the present study highlights 5-HT4 receptor stimulation as a promising therapeutic mechanism to alleviate cognitive symptoms related to MDD.
Insights
5-HT4 receptor agonists effectively reversed stress-induced cognitive deficits in a depression model. Unlike fluoxetine, this treatment improved learning and memory, suggesting a novel therapeutic avenue for major depressive disorder (MDD) cognitive symptoms.
Area of Science:
- Neuroscience
- Pharmacology
- Psychiatry
Background:
- Cognitive disturbances are significant, debilitating symptoms in major depressive disorder (MDD).
- Existing monoaminergic antidepressants do not fully address these cognitive deficits.
- The cognitive-enhancing potential of 5-HT4 receptor agonists, particularly under stress conditions, requires further investigation.
Purpose of the Study:
- To investigate the efficacy of a 5-HT4 receptor agonist in reversing stress-induced cognitive impairments in a mouse model of depression.
- To compare the effects of a 5-HT4 agonist with a standard antidepressant (fluoxetine) on cognitive function in this model.
Main Methods:
- Utilized a chronic corticosterone (CORT) mouse model to induce anxiety/depression and associated cognitive deficits.
- Administered a 5-HT4 agonist (RS67333) or fluoxetine chronically.
- Assessed cognitive function through tests evaluating episodic-like, associative, and spatial learning and memory.
Main Results:
- Chronic treatment with the 5-HT4 agonist RS67333 fully restored episodic-like, associative, and spatial learning and memory impairments induced by CORT.
- Fluoxetine only partially improved spatial learning and memory and had no effect on associative/contextual memory.
- These findings indicate distinct mechanisms of action for 5-HT4 agonists and fluoxetine regarding cognitive function.
Conclusions:
- 5-HT4 receptor stimulation demonstrates significant potential for alleviating cognitive deficits associated with MDD.
- Targeting the 5-HT4 receptor offers a promising therapeutic strategy beyond traditional monoaminergic antidepressants for cognitive symptoms in depression.
