Interactions of Corticotropin-Releasing Factor, Urocortin and Citalopram in a Primate Model of Stress-Induced Amenorrhea

Abstract

Background/Aims: We established a cynomolgus macaque model of stress-induced amenorrhea in which the application of combined metabolic and psychosocial stress suppressed ovulation in stress-sensitive (SS) individuals, but not in highly stress-resilient (HSR) individuals. We previously reported that SS monkeys have deficits in global serotonin release and serotonin-related gene expression in the raphe nucleus, and that administration of the selective serotonin reuptake inhibitor S-citalopram increased estrogen and progesterone production in SS monkeys. In this study, we questioned whether there was a difference in corticotropin-releasing factor (CRF) or urocortin (UCN) stress-related peptide systems in the midbrain raphe region when HSR and SS monkeys treated with placebo or S-citalopram are compared. Methods: Monkeys characterized as HSR or SS were administered placebo or S-citalopram for 15 weeks. CRF fibers in the dorsal raphe were detected with an antibody against human CRF. UCN1 fibers were immunostained in an area rostral to the dorsal raphe. The fibers were quantified by stereology and analyzed by two-way ANOVA. UCN1 cell bodies were counted in the supraoculomotor area near the Edinger-Westphal nucleus. Results: S-citalopram significantly decreased the CRF fiber density in SS animals, but not in HSR animals. SS monkeys had a significantly lower UCN1 fiber density compared to HSR monkeys, but S-citalopram treatment did not alter the UCN1 fiber density. SS animals treated with S-citalopram tended to have a higher number of UCN1-positive cell bodies than the other groups. Conclusion: S-citalopram decreased CRF fiber density and appears to increase the production of UCN1 in SS individuals, indicating the likelihood that serotonin is involved in regulating CRF and UCN1 in individuals who are sensitive to the effects of serotonin.

Exposure to Prenatal Psychobiological Stress Exerts Programming Influences on the Mother and Her Fetus

“…In humans, estrogen alterations due to menopause and the menstrual cycle are associated with transient alterations in brain structure [152,153]. Moreover, primates who are sensitive to stress-induced amenorrhea exhibit greater evidence of CRH activity in the paraventricular nucleus and thalamus and high CRH fiber density in the central nucleus of the amygdala than resilient animals [154]. These exposures which are of a relatively small magnitude strongly suggest that in humans, as in rodents, the massive hormonal changes of pregnancy alter brain function and morphology.…”

Effects of citalopram on serotonin and CRF systems in the midbrain of primates with differences in stress sensitivity

“…Since citalopram is a selective serotonin reuptake inhibitor, we examined its efect on serotonin-related gene expression (Lima et al, 2009). In addition, due to the involvement of the CRF system in stress and the link between serotonin and CRF, we examined CRF and UCN1 innervation of the serotonin system (Weissheimer, 2010) and CRF-R2 expression in the dorsal raphe.…”

“…It is also noteworthy that stress-sensitive animals exhibited reduced serotonin gene expression, elevated CRF in the PVN and higher CRF fiber density in the dorsal raphe nucleus in the absence of external stress (Centeno et al, 2007, Bethea et al, 2008, Weissheimer, 2010). There are numerous studies in humans indicating that childhood trauma leads to vulnerability to stress and affective disorders in adulthood (Nemeroff, 2004a), Since the cynomolgus monkeys are caught and imported, we speculate that the vulnerability of some individuals may be due to “childhood trauma” in the wild such as variable foraging demands on the mother or abuse (Coplan et al, 2010).…”

“…In situ hybridization (ISH) assays with 35 S-UTP were applied to determine the expression of TPH2, SERT and 5HT1A (Lima et al, 2009). Immunocytochemical (ICC) assays were applied to examine the innervation of the raphe by CRF and UCN1 axons as previously described (Weissheimer, 2010). Densitometric and stereological analysis was applied to quantify the ISH and ICC assays as previously described (Lima et al, 2009, Weissheimer, 2010).…”

Effect of serotonin transporter blockade on L-DOPA-induced dyskinesia in animal models of Parkinson’s disease

“…These results suggest (i) that mechanisms accounting for the antidepressant and anti-dyskinetic effects of citalopram may be partly different, (ii) that the anti-dyskinetic effect of SSRIs in PD patients may require doses of these drugs that are higher than those used to treat symptoms of depression. Indeed, a previous study showed that in female monkeys a dose of 1.2-4.8 mg/kg of citalopram given for 15 weeks elevated blood levels of this drug into the therapeutic range for treating depression in humans (Lima et al, 2009;Weissheimer et al, 2010). Although citalopram was only given acutely in our study, the effective dose, 15 mg/kg, seems to be higher than the dose needed to treat depression; however, we cannot discard the possibility that citalopram may become effective at lower doses when given chronically in the MPTP-treated macaques.…”