We have demonstrated marked differences in the neurobiology of the serotonin system between stress-sensitive (SS) and stress-resilient (SR) cynomolgus macaques characterized in a model of stress-induced amenorrhea, also called functional hypothalamic amenorrhea (FHA). Dysfunction of the serotonin system in SS monkeys suggested that administration of a selective serotonin reuptake inhibitor (SSRI) might correct FHA. This study examines the effect of escitalopram (CIT) administration to SS and SR monkeys on corticotrophin-releasing factor (CRF) receptor 1 (CRF-R1) and CRF receptor 2 (CRF-R2) gene expression in the serotonin cell body region of the midbrain dorsal raphe. CRF-R1 was not significantly different between groups. There was a significant effect of treatment and a significant interaction between treatment and stress sensitivity on the average CRF-R2-positive pixel area (P < .004 and P < .006, respectively) and on the average number of CRF-R2-positive cells (P < .023 and P < .025, respectively). CIT significantly increased CRF-R2-positive pixel area and cell number in the SS group (pixel area P < .001; cell number P < .01; Bonferoni) but not in the SR group. In summary, CIT administration tended to decrease CRF-R1, but the small animal number precluded significance. CIT administration significantly increased CRF-R2 only in SS animals. These data suggest that the administration of CIT reduces anxiogenic components and increases anxiolytic components of the CRF system in the midbrain serotonin network, which in turn leads to improved ovarian function. Moreover, these data raise the possibility that SSRIs may be effective in the treatment of stress-induced infertility.
FioroniLFavaMGenazzaniADFacchinettiFGenazzaniAR. Life events impact in patients with secondary amenorrhoea. J Psychosom Res. 1994; 38(6): 617–622.
5.
LaughlinGADominguezCEYenSS. Nutritional and endocrine-metabolic aberrations in women with functional hypothalamic amenorrhea. J Clin Endocrinol Metab. 1998; 83(1): 25–32.
6.
BergaSLMarcusMDLoucksTLHlastalaSRinghamRKrohnMA. Recovery of ovarian activity in women with functional hypothalamic amenorrhea who were treated with cognitive behavior therapy. Fertil Steril. 2003; 80(4): 976–981.
7.
TschugguelWBergaSL.Treatment of functional hypothalamic amenorrhea with hypnotherapy. Fertil Steril. 2003; 80(4): 982–985.
8.
BetheaCLCentenoMLCameronJL. Neurobiology of stress-induced reproductive dysfunction in female macaques. Mol Neurobiol. 2008; 38(3): 199–230.
9.
LinthorstAC.Interactions between corticotropin-releasing hormone and serotonin: implications for the aetiology and treatment of anxiety disorders. Handb Exp Pharmacol. 2005; 169: 181–204.
10.
LuitenPGter HorstGJKarstHSteffensAB. The course of paraventricular hypothalamic efferents to autonomic structures in medulla and spinal cord. Brain Res. 1985; 329: 374–8.
11.
RuggieroDAUnderwoodMDRicePMMannJJArangoV. Corticotropic-releasing hormone and serotonin interact in the human brainstem: behavioral implications. Neuroscience. 1999; 91(4): 1343–1354.
12.
DautzenbergFMHaugerRL. The CRF peptide family and their receptors: yet more partners discovered. Trends Pharmacol Sci. 2002; 23(2): 71–77.
13.
VaughanJDonaldsonCBittencourtJ. Urocortin, a mammalian neuropeptide related to fish urotensin I and to corticotropin-releasing factor. Nature. 1995; 378(6554): 287–292.
14.
LukkesJLForsterGLRennerKJSummersCH. Corticotropin-releasing factor 1 and 2 receptors in the dorsal raphe differentially affect serotonin release in the nucleus accumbens. Eur J Pharmacol. 2008; 578(2-3): 185–193.
15.
ValdezGRInoueKKoobGFRivierJValeWZorrillaEP. Human urocortin II: mild locomotor suppressive and delayed anxiolytic-like effects of a novel corticotropin-releasing factor related peptide. Brain Res. 2002; 943(1): 142–150.
16.
AzmitiaECGannonPJ. The primate serotonergic system: a review of human and animal studies and a report on Macaca fascicularis. Adv Neurol. 1986; 43: 407–468.
17.
JacobsBLAzmitiaEC. Structure and function of the brain serotonin system. Physiolog Rev. 1992; 72(1): 165–231.
18.
BetheaCLCentenoML. Ovarian steroid treatment decreases corticotropin-releasing hormone (CRH) mRNA and protein in the hypothalamic paraventricular nucleus of ovariectomized monkeys. Neuropsychopharmacology. 2008; 33(3): 546–556.
19.
CentenoMLSanchezRLReddyAPCameronJLBetheaCL. Corticotropin-releasing hormone and pro-opiomelanocortin gene expression in female monkeys with differences in sensitivity to stress. Neuroendocrinology. 2007; 86(4): 277–288.
20.
FullerRW. The involvement of serotonin in regulation of pituitary-adrenocortical function. Front Neuroendocrinol. 1992; 13(3): 250–270.
21.
MichelsenKASchmitzCSteinbuschHW. The dorsal raphe nucleus–from silver stainings to a role in depression. Brain Res Rev. 2007; 55(2): 329–242.
22.
ClarkMSKaiyalaKJ. Role of corticotropin-releasing factor family peptides and receptors in stress-related psychiatric disorders. Semin Clin Neuropsychiatry. 2003; 8(2): 119–136.
23.
ReulJMHolsboerF. Corticotropin-releasing factor receptors 1 and 2 in anxiety and depression. Curr Opin Pharmacol. 2002; 2(1): 23–33.
24.
MaierSFWatkinsLR. Stressor controllability and learned helplessness: the roles of the dorsal raphe nucleus, serotonin, and corticotropin-releasing factor. Neurosci Biobehav Rev. 2005; 29(4-5): 829–841.
25.
VaswaniMLindaFKRameshS. Role of selective serotonin reuptake inhibitors in psychiatric disorders: a comprehensive review. Prog Neuropsychopharmacol Biol Psychiatry. 2003; 27(1): 85–102.
26.
LiXFBoweJEKinsey-JonesJSBrainSDLightmanSLO'ByrneKT. Differential role of corticotrophin-releasing factor receptor types 1 and 2 in stress-induced suppression of pulsatile luteinising hormone secretion in the female rat. J Neuroendocrinol. 2006; 18(8): 602–610.
27.
RivierCRivierJValeW. Stress-induced inhibition of reproductive functions: role of endogenous corticotropin-releasing factor. Science. 1986; 231(4738): 607–609.
28.
BetheaCLPauFKFoxSHessDLBergaSLCameronJL. Sensitivity to stress-induced reproductive dysfunction linked to activity of the serotonin system. Fertil Steril. 2005; 83(1): 148–155.
29.
LimaFBCentenoMLCostaMEReddyAPCameronJLBetheaCL. Stress sensitive female macaques have decreased fifth Ewing variant (Fev) and serotonin-related gene expression that is not reversed by citalopram. Neuroscience. 2009; 164(2): 676–691.
30.
BetheaCLStreicherJMMirkesSJSanchezRLReddyAPCameronJL. Serotonin-related gene expression in female monkeys with individual sensitivity to stress. Neuroscience. 2005; 132(1): 151–166.
31.
WeissheimerKVHerodSMCameronJLBetheaCL. Interactions of corticotropin-releasing factor, urocortin and citalopram in a primate model of stress-induced amenorhea. Neuroendocrinology. 2010; 92(4): 224–234.
32.
CameronJLBythewayJAGuayS. Treatment with a serotonin reuptake inhibitor increases reproductive hormone secretion in stress sensitive monkeys. 34th Annual Meeting of the Society for Neuroscience. San Diego, CA, 2004; Society for Neuroscience. Abstract 192.18.
33.
Berg-von der EmdeKDeesWLHineyJK. Neurotrophins and the neuroendocrine brain: different neurotrophins sustain anatomically and functionally segregated subsets of hypothalamic dopaminergic neurons. J Neurosci. 1995; 15(6): 4223–4237.
34.
BergaSLLoucksTL. Use of cognitive behavior therapy for functional hypothalamic amenorrhea. Ann N Y Acad Sci. 2006; 1092: 114–129.
35.
ReameNESauderSECaseGDKelchRPMarshallJC. Pulsatile gonadotropin secretion in women with hypothalamic amenorrhea: evidence that reduced frequency of gonadotropin-releasing hormone secretion is the mechanism of persistent anovulation. J Clin Endocrinol Metab. 1985; 61(5): 851–858.
36.
BergaSLLoucksTL. The diagnosis and treatment of stress-induced anovulation. Minerva Ginecol. 2005; 57(1): 45–54.
37.
AliMKLamRW. Comparative efficacy of escitalopram in the treatment of major depressive disorder. Neuropsychiatr Dis Treat. 2011; 7: 39–49.
38.
PortellaMJde Diego-AdelinoJBallesterosJ. Can we really accelerate and enhance the selective serotonin reuptake inhibitor antidepressant effect? a randomized clinical trial and a meta-analysis of pindolol in nonresistant depression. J Clin Psychiatry. 2010; 72(7): 962–969.
39.
EntsuahARHuangHThaseME. Response and remission rates in different subpopulations with major depressive disorder administered venlafaxine, selective serotonin reuptake inhibitors, or placebo. J Clin Psychiatry. 2001; 62(11): 869–877.
40.
KirbyLGRiceKCValentinoRJ. Effects of corticotropin-releasing factor on neuronal activity in the serotonergic dorsal raphe nucleus. Neuropsychopharmacology. 2000; 22(2): 148–162.
41.
PernarLCurtisALValeWWRivierJEValentinoRJ. Selective activation of corticotropin-releasing factor-2 receptors on neurochemically identified neurons in the rat dorsal raphe nucleus reveals dual actions. J Neurosci. 2004; 24(6): 1305–1311.
42.
MüllerMBZimmermannSSillaberI. Limbic corticotropin-releasing hormone receptor 1 mediates anxiety-related behavior and hormonal adaptation to stress. Nat Neurosci. 2003; 6(10): 1100–1107.
43.
BaileyJEPapadopoulosADiaperA. Preliminary evidence of anxiolytic effects of the CRF1 receptor antagonist R317573 in the 7.5% CO2 proof-of-concept experimental model of human anxiety. J Psychopharmacol. 2011; 25(9): 1199–1206 [Epub ahead of print].
44.
LicinioJO'KirwanFIrizarryK. Association of a corticotropin-releasing hormone receptor 1 haplotype and antidepressant treatment response in Mexican-Americans. Mol Psychiatry. 2004; 9(12): 1075–1082.
45.
HerodSMBythewayJDolneyRCameronJL. Female monkeys who are sensitive to stress-induced reproductive dysfunction also show increases in certain forms of anxious behavior. 36th Annual Meeting of the Society for Neuroscience. Atlanta, GA, 2006; Society for Neuroscience. Abstract #257.22.
46.
KirbyLGFreeman-DanielsELemosJC. Corticotropin-releasing factor increases GABA synaptic activity and induces inward current in 5-hydroxytryptamine dorsal raphe neurons. J Neurosci. 2008; 28(48): 12927–12937.
47.
DayHEGreenwoodBNHammackSE. Differential expression of 5HT-1A, alpha 1b adrenergic, CRF-R1, and CRF-R2 receptor mRNA in serotonergic, gamma-aminobutyric acidergic, and catecholaminergic cells of the rat dorsal raphe nucleus. J Comp Neurol. 2004; 474(3): 364–378.
48.
HerodSCameronJL. Female monkeys sensitive to stress-induced reproductive dysfunction have low central drive to the reproductive axis in nonstressed conditions. Annual Meeting of the Endocrine Society. Toronto, Canada, 2007; Endocrine Society. Abstract P2-467.
49.
HerodSMPohlCRCameronJL. Treatment with a CRH-R1 antagonist prevents stress-induced suppression of the central neural drive to the reproductive axis in female macaques. Am J Physiol Endocrinol Metab. 2011; 300(1): E19–E27.
50.
BergaSLGirtonLG. The psychoneuroendocrinology of functional hypothalamic amenorrhea. Psychiatr Clin North Am. 1989; 12(1): 105–116.
51.
BetheaCLLimaFBCentenoML. Effects of citalopram on serotonin and CRF systems in the midbrain of primates with differences in stress sensitivity. J Chem Neuroanat. 2011; 41(4): 200–218.
