Prenatal Excess Glucocorticoid Exposure and Adult Affective Disorders:A Role for Serotonergic and Catecholamine Pathways

Fetal glucocorticoid exposure is a key mechanism proposed to underlie prenatal ‘programming’ of adult affective behaviours such as depression and anxiety. Indeed, the glucocorticoid metabolising enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is highly expressed in the placenta and the developing fetus, acts as a protective barrier from the high maternal glucocorticoids which may alter developmental trajectories. The programmed changes resulting from maternal stress or bypass or from the inhibition of 11β-HSD2 are frequently associated with alterations in the hypothalamic-pituitary-adrenal (HPA) axis. Hence, circulating glucocorticoid levels are increased either basally or in response to stress accompanied by CNS region-specific modulations in the expression of both corticosteroid receptors (mineralocorticoid and glucocorticoid receptors). Furthermore, early-life glucocorticoid exposure also affects serotonergic and catecholamine pathways within the brain, with changes in both associated neurotransmitters and receptors. Indeed, global removal of 11β-HSD2, an enzyme that inactivates glucocorticoids, increases anxiety‐ and depressive-like behaviour in mice; however, in this case the phenotype is not accompanied by overt perturbation in the HPA axis but, intriguingly, alterations in serotonergic and catecholamine pathways are maintained in this programming model. This review addresses one of the potential adverse effects of glucocorticoid overexposure in utero, i.e. increased incidence of affective behaviours, and the mechanisms underlying these behaviours including alteration of the HPA axis and serotonergic and catecholamine pathways

Involvement of Nitric Oxide, Neurotrophins and HPA Axis in Neurobehavioural Alterations Induced by Prenatal Stress

Several studies suggest that negative emotions during pregnancy generate adverse effects on the cognitive, behavioural and emotional development of the descendants. The psychoneuroendocrine pathways involve the transplacentary passage of maternal glucocorticoids in order to influence directly on fetal growth and brain development. Nitric oxide is a gaseous neurotransmitter that plays an important role in the control of neural activity by diffusing into neurons and participates in learning and memory processes. It has been demonstrated that nitric oxide is involved in the regulation of corticosterone secretion. Thus, it has been found that the neuronal isoform of nitric oxide synthase (nNOS) is an endogenous inhibitor of glucocorticoid receptor (GR) in the hippocampus and that nNOS in the hippocampus may participate in the modulation of hypothalamic–pituitary–adrenal axis activity via GR. Neurotrophins are a family of secreted growth factors consisting of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and NT4. Although initially described in the nervous system, they regulate processes such as cell survival, proliferation and differentiation in several other compartments. It has been demonstrated that the NO–citrulline cycle acts together with BDNF in maintaining the progress of neural differentiation. In the present chapter, we explore the interrelation between nitric oxide, glucocorticoids and neurotrophins in brain areas that are key structures in learning and memory processes. The participation of this interrelation in the behavioural and cognitive alterations induced in the offspring by maternal stress is also addressed.Fil: Maur, Damián Gustavo. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Pascuan, Cecilia G.. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Genaro, Ana Maria. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Zorrilla Zubilete, María Aurelia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentin