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

Abstract

This chapter reviews the neurobiological effects of stress sensitivity and CIT treatment observed in our nonhuman primate model of Functional Hypothalamic Amenorrhea (FHA). This type of infertility, also known as stress-induced amenorrhea, is exhibited by cynomolgus macaques. In small populations, some individuals are stress sensitive (SS) and others are highly stress resilient (HSR). The SS macaques have suboptimal secretion of estrogen and progesterone during normal menstrual cycles. SS monkeys also have decreased serotonin gene expression and increased CRF expression compared to HSR monkeys. Recently, we found that s-citalopram (CIT) treatment improved ovarian steroid secretion in SS monkeys, but had no effect in HSR monkeys. Examination of the serotonin system revealed that SS monkeys had significantly lower Fev (fifth Ewing variant, rodent Pet1), TPH2 (tryptophan hydroxylase 2), 5HT1A autoreceptor and SERT (serotonin reuptake transporter) expression in the dorsal raphe than SR monkeys. However, CIT did not alter the expression of either Fev, TPH2, SERT or 5HT1A mRNAs. In contrast, SS monkeys tended to a higher density of CRF fiber innervation of the dorsal raphe than HSR monkeys, and CIT significantly decreased the CRF fiber density in SS animals. In addition, CIT increased CRF-R2 gene expression in the dorsal raphe. We speculate that in a 15-week time frame, the therapeutic effect of S-citalopram may be achieved through a mechanism involving extracellular serotonin inhibition of CRF and stimulation of CRF-R2, rather than alteration of serotonin-related gene expression.

Corticotropin releasing hormone and imaging, rethinking the stress axis

“…These findings may determine trait and/or state vulnerability to stress sensitivity and resistance [33]. They show differential neurochemical and anatomic changes in SS/SR based on cell density and molecular expression associated with phenotypic stress resistance or sensitivity [34, 35]. These highly complex but expected patterns of integration are consistent with our limited imaging signals when viewed en mass.…”

The regulation of reproductive neuroendocrine function by insulin and insulin-like growth factor-1 (IGF-1)

“…Stress sensitive monkeys were found to have increased cellular content of GnRH coupled with reduced GnRH fiber density at the median eminence (Centeno et al 2007b), reflecting reduced secretory activity (Herod et al 2011b). Using this model allowed investigators to identify a key role for impaired serotonin function (Lima et al 2009, Centeno et al 2007a) which, in turn, produces changes in the neural circuitries controlling the hypothalamic-pituitary-adrenal stress axis (Herod et al 2011a, Bethea et al 2011). …”

Behavioral and neurobiological characteristics of social stress versus depression in nonhuman primates

“…Stress responsive monkeys were defined as those with the most impairment to ovarian function during the stress. Under nonstress conditions, these stress sensitive monkeys had lower ovarian steroid secretion during normal (nonstressed) menstrual cycles, lower serotonergic function in response to fenfluramine, fewer serotonin neurons, lower expression of pivotal serotonin-related genes, lower expression of 5HT2A and 2C genes in the hypothalamus, higher gene expression of GAD67 and CRH in the hypothalamus, reduced gonadotropin-releasing hormone transport to the anterior pituitary and higher basal heart rates (Centeno et al, 2007; Bethea et al, 2008, 2011). …”