CMS leads to a long-term altered behavioral profile that could be partially reverted by chronic antidepressant treatment. This study brings novel features regarding the long-term effects of CMS and on the predictive validity of this depression animal model.

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BACKGROUND AND PURPOSEStress is believed to be associated with the development of neuropsychiatric disorders, including Alzheimer's disease (AD). We have studied mechanisms implicated in vulnerability to stress and the relationship with changes in AD-related markers. EXPERIMENTAL APPROACHAnhedonia induced by a chronic mild stress (CMS) procedure, applied for 6 weeks, was used to select rats vulnerable or resistant to stress. Sucrose intake, the Porsolt forced swimming test and cognitive deficits in the novel object recognition test (NORT) were used to characterize vulnerable and resilient rats. The antidepressant venlafaxine (20 mg·kg -1 p.o.) or saline was administered daily during the last 2 weeks of CMS. Biochemical markers affected by stress, PKB, ERK and synaptophysin, and those associated with AD, amyloid b-protein (Ab), b-secretase (BACE1) and t phosphorylation, were measured in the hippocampus. KEY RESULTSAfter CMS, 40% of rats were resistant to the development of anhedonia (CMS-resistant to stress), whereas the remaining were responsive [CMS-anhedonic (CMSA)]. Only CMSA rats displayed significant increases in immobility time in the forced swimming test and cognitive deficits in the NORT, and significant decreases in synaptophysin, phosphorylated PKB and phosphorylated ERK1/2 expression in the hippocampus. Increased levels of Ab40, BACE1 and t phosphorylation were also found only in CMSA rats. All these effects in CMSA rats were reverted by treatment with venlafaxine. CONCLUSIONS AND IMPLICATIONSVulnerability to stress might constitute a risk factor for the development of AD, and pharmacological treatment with venlafaxine may represent a therapeutic strategy for the treatment of stress-related disorders, including AD.

It is becoming evident that chronic exposure to glucocorticoids might not only result in insulin resistance or cognitive deficits, but also is considered as a risk factor for pathologies such as depression or Alzheimer's disease. In the present study, in vivo experiments using a non-invasive method of chronic administration of corticosterone in drinking water demonstrated that chronic corticosterone administration led to cognitive impairment in the novel object recognition test and insulin resistance, as shown by significant increases in plasma insulin levels and the homeostatic model assessment index, and decreased insulin receptor phosphorylation. Corticosterone treatment induced an increased expression of stress-activated c-Jun N-terminal kinase (JNK) in the hippocampus, accompanied by decreases in glycogen synthase kinase 3β, increases in pTau levels and increased neuronal cell death (caspase-3 activity). All these effects were reversed by the administration of a JNK1 inhibitor or by the mineralocorticoid receptor antagonist spironolactone. It is suggested that the mineralocorticoid receptors and JNK-mediated pathways are involved in the interaction of glucocorticoid-insulin resistance and the development of relevant cellular processes for Alzheimer's disease.