Stress sensitive female macaques have decreased fifth Ewing variant (Fev) and serotonin-related gene expression that is not reversed by citalopram

• Published in: Neuroscience Vol. 164; no. 2; pp. 676 - 691
• Main Authors: Lima, F.B, Centeno, M.L, Costa, M.E, Reddy, A.P, Cameron, J.L, Bethea, C.L
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.12.2009; Elsevier
• Subjects: 5HT1A autoreceptor; Animals; Antidepressive Agents, Second-Generation - blood; Antidepressive Agents, Second-Generation - pharmacology; Biological and medical sciences; citalopram; Citalopram - blood; Citalopram - pharmacology; Cynomolgus; Female; Fev; Fundamental and applied biological sciences. Psychology; Gene Expression; Macaca; Macaca fascicularis; Neurology; Pons - drug effects; Pons - metabolism; Proto-Oncogene Proteins c-ets - genetics; Proto-Oncogene Proteins c-ets - metabolism; Raphe Nuclei - drug effects; Raphe Nuclei - metabolism; Receptor, Serotonin, 5-HT1A - genetics; Receptor, Serotonin, 5-HT1A - metabolism; RNA, Messenger - metabolism; serotonin; Serotonin Plasma Membrane Transport Proteins - genetics; Serotonin Plasma Membrane Transport Proteins - metabolism; serotonin reuptake transporter; Species Specificity; Stress, Psychological - drug therapy; Stress, Psychological - genetics; Stress, Psychological - metabolism; tryptophan hydroxylase; Tryptophan Hydroxylase - genetics; Tryptophan Hydroxylase - metabolism; Vertebrates: nervous system and sense organs; TPH2; tryptophan hydroxylase 2; functional hypothalamic amenorrhea; HRT; highly stress resilient; serotonin reuptake transporter; serotonin; selective serotonin reuptake inhibitor; very stress sensitive; analysis of variance; ANOVA; OD; tryptophan hydroxylase; citalopram; placebo; ribonuclease A; ISH; RNase; SS; medium stress resilient; SSC; saline sodium citrate; 5HT1A autoreceptor; HSR; fifth Ewing variant; MSR; CIT; SSRI; SERT; Fev; stress sensitive; VSS; hormone replacement therapy; PL; optical density; FHA; in situ hybridization; Serotonin; Enzyme; Autoreceptor; Gene expression; Stress; Citalopram; Serotonin transporter; Tryptophan 5-monooxygenase; Neurotransmitter; Female; Oxidoreductases
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2009.08.010

Abstract Female cynomolgus monkeys exhibit different degrees of reproductive dysfunction with moderate metabolic and psychosocial stress. When stressed with a paradigm of relocation and diet for 60 days or two menstrual cycles, highly stress resilient monkeys (HSR) continued to ovulate during the stress cycles whereas stress sensitive monkeys (SS) did not. After cessation of stress, monkeys characterized as HSR or SS were administered placebo (PL) or S-citalopram (CIT) for 15 weeks at doses that normalized ovarian steroid secretion in the SS animals and that maintained blood CIT levels in a therapeutic range. After euthanasia, the brain was perfused with 4% paraformaldehyde. The pontine midbrain was blocked and sectioned at 25 μm. The expression of four genes pivotal to serotonin neural function was assessed in the four groups of monkeys ( n =4/group). Fev (fifth Ewing variant) ETS transcription factor, tryptophan hydroxylase 2 (TPH2), the serotonin reuptake transporter (SERT), and the 5HT1A autoreceptor were determined at 7–8 levels of the dorsal raphe nucleus with in situ hybridization (ISH) using radiolabeled- and digoxygenin-incorporated riboprobes. Positive pixel area and cell number were measured with Slidebook 4.2 in the digoxigenin assay for Fev. Optical density (OD) and positive pixel area were measured with NIH Image software in the radiolabeled assays for TPH2, SERT and 5HT1A. All data were analyzed with two-way ANOVA. SS monkeys had significantly fewer Fev-positive cells and lower Fev-positive pixel area in the dorsal raphe than HSR monkeys. SS monkeys also had significantly lower levels of TPH2, SERT and 5HT1A mRNAs in the dorsal raphe nucleus than HSR monkeys. However, CIT did not alter the expression of either Fev, TPH2, SERT or 5HT1A mRNAs. These data suggest that SS monkeys have fewer serotonin (5-HT) neurons than HSR monkeys, and that they have deficient Fev expression, which in turn, leads to deficient TPH2, SERT and 5HT1A expression. In addition, the therapeutic effect of CIT is probably achieved through mechanisms other than alteration of 5-HT-related gene expression.