Fluoxetine, not donepezil, reverses anhedonia, cognitive dysfunctions and hippocampal proteome changes during repeated social defeat exposure.

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.

Increased corticotropin-releasing factor concentrations in the bed nucleus of the stria terminalis of anhedonic rats.

Chronic mild stress in rats is an antidepressant-responsive model for anhedonic symptoms of major depression. Many patients with depression exhibit alterations in hypothalamic-pituitary-adrenal axis activity, and corticotropin-releasing factor (CRF) neuronal function. This study investigated the potential involvement of CRF and CRF receptors in the development of chronic mild stress-induced anhedonia in rats. Rats were subjected to 19 days of chronic mild stress, during which time anhedonia was periodically assessed by determining the threshold for self-stimulation of the ventral tegmental area. Anhedonic rats exhibited a 50% increase in CRF concentrations in the bed nucleus of the stria terminalis compared to control rats. There were no significant changes in hypothalamic-pituitary-adrenal axis activity, CRF or CRF(1) receptor mRNA expression, or CRF receptor binding in the brain regions analyzed. Though preliminary, these results are consistent with the hypothesis that chronic stress-induced modulation of CRF function in specific brain structures such as the bed nucleus of the stria terminalis may contribute to the pathophysiology of depression.

5HT2C receptor agonists exhibit antidepressant-like properties in the anhedonia model of depression in rats.

Potential antidepressant properties of preferential 5HT2C receptor agonists were investigated in stress-induced anhedonia, a validated simulation of depression. This simulation evaluates the hedonic state of stressed rats by recording variations in self-stimulation threshold measured before, during, and after exposure to intermittent, unpredictable, mild stressors. This stress regimen gradually elevates self-stimulation threshold, suggesting the development of an anhedonic state. In stressed animals, chronic treatment with the preferential 5HT2C receptor agonists Ro 60-0175 and Ro 60-0332 (3 mg/kg i.p. b.i.d.) prevented the loss of sensitivity to reward. Similarly, when stressed anhedonic animals were curatively treated with Ro 60-0175 (3 mg/kg i.p. b.i.d.), the stress-induced anhedonia was gradually reversed. These results suggest a role for 5HT2C receptors in some aspects of depression, and potential antidepressant properties for selective 5HT2C receptor agonists. Such compounds may offer an innovative approach to the treatment of mood disorders.

Curative effects of the atypical antidepressant mianserin in the chronic mild stress-induced anhedonia model of depression.

This study was designed to validate a novel animal model of depression by testing the curative effects of the atypical antidepressant mianserin. In this paradigm, the hedonic state of rats was assessed using an intracranial self-stimulation (ICSS) procedure. The ICSS threshold was determined before, during and after a 38-day period of exposure to a variety of intermittent, unpredictable, mild stressors. After 11 days of this regimen, the ICSS threshold was significantly higher in the stressed rats, suggesting a gradual decrease of sensitivity to reward. This "anhedonia" lasted throughout the stress regimen and progressively diminished over a 20-day period after stress was terminated. When stressed animals exhibiting anhedonia were treated with mianserin, the stress-induced increase in the ICSS threshold was gradually reversed over ten days of treatment. These results provide further support for the value of this anhedonia paradigm in modelling an important aspect of human depressive disorders.

Effects of moclobemide, a new generation reversible Mao-A inhibitor, in a novel animal model of depression.

This study was designed to investigate the predictive validity of a recently described chronic mild-stress-induced anhedonia model of depression. In an intracranial self-stimulation (ICSS) paradigm, rats were allowed to self-stimulate in the ventral tegmental area. Stimulation frequency thresholds for ICSS responses were determined prior to, during, and after a 19-day period of exposure to a variety of mild, intermittent, unpredictable stressors. After nine days of mild stress, stimulation threshold was significantly increased, suggesting a gradual decrease in the rewarding properties of brain stimulation. This anhedonic state lasted throughout the stress period and slowly disappeared over a 10-day period after termination of the stress regimen. This stress-induced increase in ICSS threshold was not observed in rats that were stressed and concomitantly treated with the reversible inhibitor of monoamine oxidase type A (RIMA) moclobemide (20 mg/kg, b.i.d.). In nonstressed animals treated with vehicle or moclobemide, no significant change in ICSS occurred during the course of the experiment. These experimental results reinforce the value of this animal model with respect to its predictive and construct validity.

Antidepressant treatment prevents chronic unpredictable mild stress-induced anhedonia as assessed by ventral tegmentum self-stimulation behavior in rats.

The effect of chronic unpredictable mild stress on sensitivity to reward was evaluated using the brain self-stimulation procedure. Rats were allowed to electrically self-stimulate the ventral tegmental area, one of the main cerebral structures subserving positive reinforcement. Stimulation thresholds (frequency of stimuli) for self-stimulation responses were determined prior to, during, and following a 19-day period of exposure to a variety of mild unpredictable stressors. Stimulation threshold was increased in stressed rats, suggesting a decrease in the rewarding properties of brain stimulation. This deficit became evident after about 1 week of mild stress, lasted throughout the stress period, and progressively diminished following termination of the stress regime. In stressed rats concomitantly treated with the tricyclic antidepressant desipramine (5 mg/kg b.i.d.), no stress-induced increase in self-stimulation threshold was observed. However, desipramine did not modify self-stimulation threshold in non-stressed animals. Thus, the increased threshold for brain self-stimulation produced by a period of chronic unpredictable mild stress can be completely prevented by concomitant antidepressant treatment and may provide an heuristic animal model of depression.