Failure to mount adaptive responses to stress results in dysregulation and cell death in the midbrain raphe.

Stress is a common trigger in affective disorder onset, yet the mechanism and predisposing factors of vulnerability remain unknown. Effective disease prevention requires a critical balance of responses within the serotonergic raphe nucleus, including a coordination of corticotropin-releasing factor (CRF) actions at both of its receptors, CRF receptor-1 and CRF receptor-2. Mice deficient in CRF receptor-2 (R2KO) were used as a model of maladaptive stress responsivity to examine the physiological and molecular markers of stress dysregulation within the raphe in the absence of this receptor. After chronic stress, R2KO mice failed to display the robust stress-mediated adaptations characteristic of control mice, including elevations in tryptophan hydroxylase-2 and CRF receptor-1 expression and concordant increases in behavioral arousal. As a further indication of failed homeostatic mechanisms, R2KO mice displayed indices of cell death in the raphe after stress exposure, with elevations in proapoptotic factors but a failure to mount adaptive increases in antiapoptotic factors found in control mice. In vitro electrophysiological characterization of the specific influence of CRF on the raphe revealed both basal differences and a failure to respond to CRF administration in R2KO mice. These results support a requirement for homeostatic maintenance in response to stress in the raphe, where dysregulation may be a critical predictor of affective disorder onset.

Influence of sex and corticotropin-releasing factor pathways as determinants in serotonin sensitivity.

Stress sensitivity and sex are predictive factors in affective disorder susceptibility. Serotonin (5-HT) pathway recruitment by corticotropin-releasing factor (CRF) during stress is necessary in adaptive coping behaviors, but sex differences in such responses have not been investigated. Using selective 5-HT reuptake inhibitor (SSRI) administration to acutely elevate 5-HT in a genetic model of stress sensitivity, we examined behavioral and physiological responses in male and female stress-sensitive CRF receptor-2-deficient (R2KO) mice. Chronic SSRI treatment was used to confirm outcomes were specific to acute 5-HT elevation and not antidepressant efficacy. We hypothesized that R2KO mice would show a greater sensitivity to acute changes in 5-HT and that, because females typically are more stress sensitive, R2KO females would be the most responsive. Our results supported this hypothesis because females of both genotypes and R2KO males showed a greater sensitivity to an acute 10 mg/kg dose of citalopram in a tail suspension test, displaying decreased immobile time and increased latency to immobility. Furthermore, acute citalopram promoted significant anxiogenic-like effects that were specific to R2KO females in the elevated plus maze and light-dark box tests. Chronic citalopram did not produce these behavioral changes, supporting specificity to acute 5-HT modulation. Mechanistically, females had decreased hippocampal 5-HT transporter (SERT) levels, whereas R2KO mice showed reduced SERT in the prefrontal cortex, supporting a possible intersection of sex and genotype where R2KO females would have the lowest SERT to be blocked by the SSRI. This sensitivity to 5-HT-mediated anxiety in females may underlie a heightened vulnerability to stress-related affective disorders.