Influence of Sex and Corticotropin-Releasing Factor Pathways as Determinants in Serotonin Sensitivity

• Published in: Endocrinology (Philadelphia) Vol. 150; no. 8; pp. 3709 - 3716
• Main Authors: McEuen, Jonathan G, Semsar, Katharine A, Lim, Maria A, Bale, Tracy L
• Format: Journal Article
• Language: English
• Published: Chevy Chase, MD Endocrine Society 01.08.2009; The Endocrine Society
• Subjects: Animals; Autoradiography; Biological and medical sciences; Citalopram - pharmacology; Corticotropin-Releasing Hormone - metabolism; Corticotropin-Releasing Hormone - physiology; Female; Fundamental and applied biological sciences. Psychology; Genotype; Hindlimb Suspension; Male; Maze Learning - drug effects; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Receptors, Corticotropin-Releasing Hormone - genetics; Receptors, Corticotropin-Releasing Hormone - physiology; Serotonin - metabolism; Serotonin - physiology; Serotonin Plasma Membrane Transport Proteins - metabolism; Serotonin Uptake Inhibitors - pharmacology; Sex Factors; Vertebrates: endocrinology; Hypothalamic hormone; Neurotransmitter; Sensitivity; Serotonin; Hormone releasing factor; Corticotropin releasing factor
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2008-1721

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. An increased sensitivity to acute selective serotonin re-uptake inhibitor administration may be a predictive marker of an underlying vulnerability to disease.