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

This chapter reviews the neurobiological effects of stress sensitivity and s-citalpram (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 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 have 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.

► Monkeys were characterized as stress-sensitive or stress-resilient by their ovulatory response during metabolic and psychosocial stress.
► Stress-sensitive monkeys showed an improvement in ovarian function after 15 weeks of citalopram treatment.
► Stress-sensitive monkeys have reduced gene expression of Fev, TPH2, SERT and 5HT1A compared to stress-resilient monkeys.
► Citalopram treatment did not improve Fev, TPH2, SERT or 5HT1A gene expression in stress-sensitive monkeys.
► Stress-sensitive monkeys have greater CRF fiber density and less CRF-R2 expression in the raphe compared to stress-resilient monkeys.
► Citalopram treatment decreased CRF fiber density and increased CRF-R2 expresssion in the dorsal raphe of stress-sensitive monkeys.