Effects of fluoxetine on CRF and CRF1 expression in rats exposed to the learned helplessness paradigm.

Rationale: Stress is a common antecedent reported by people suffering major depression. In these patients, extrahypothalamic brain areas, like the hippocampus and basolateral amygdala (BLA), have been found to be affected. The BLA synthesizes CRF, a mediator of the stress response, and projects to hippocampus. The main hippocampal target for this peptide is the CRF subtype 1 receptor (CRF1). Evidence points to a relationship between dysregulation of CRF/CRF1 extrahypothalamic signaling and depression.

Objective: Because selective serotonin reuptake inhibitors (SSRIs) are the first-line pharmacological treatment for depression, we investigated the effect of chronic treatment with the SSRI fluoxetine on long-term changes in CRF/CRF1 signaling in animals showing a depressive-like behavior.

Methods: Male Wistar rats were exposed to the learned helplessness paradigm (LH). After evaluation of behavioral impairment, the animals were treated with fluoxetine (10 mg/kg i.p.) or saline for 21 days. We measured BLA CRF expression with RT-PCR and CRF1 expression in CA3 and the dentate gyrus of the hippocampus with in situ hybridization. We also studied the activation of one of CRF1's major intracellular signaling targets, the extracellular signal-related kinases 1 and 2 (ERK1/2) in CA3.

Results: In saline-treated LH animals, CRF expression in the BLA increased, while hippocampal CRF1 expression and ERK1/2 activation decreased. Treatment with fluoxetine reversed the changes in CRF and CRF1 expressions, but not in ERK1/2 activation.

Conclusion: In animals exposed to the learned helplessness paradigm, there are long-term changes in CRF and CRF1 expression that are restored with a behaviorally effective antidepressant treatment.