Prenatal Stress Alters Progestogens to Mediate Susceptibility to Sex-Typical, Stress-Sensitive Disorders, such as Drug Abuse: A Review

Abstract

Maternal–offspring interactions begin prior to birth. Experiences of the mother during gestation play a powerful role in determining the developmental programming of the central nervous system. In particular, stress during gestation alters developmental programming of the offspring resulting in susceptibility to sex-typical and stress-sensitive neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. However, neither these effects, nor the underlying mechanisms, are well understood. Our hypothesis is that allopregnanolone, during gestation, plays a particularly vital role in mitigating effects of stress on the developing fetus and may mediate, in part, alterations apparent throughout the lifespan. Specifically, altered balance between glucocorticoids and progestogens during critical periods of development (stemming from psychological, immunological, and/or endocrinological stressors during gestation) may permanently influence behavior, brain morphology, and/or neuroendocrine-sensitive processes. 5α-reduced progestogens are integral in the developmental programming of sex-typical, stress-sensitive, and/or disorder-relevant phenotypes. Prenatal stress (PNS) may alter these responses and dysregulate allopregnanolone and its normative effects on stress axis function. As an example of a neurodevelopmental, neuropsychiatric, and/or neurodegenerative process, this review focuses on responsiveness to drugs of abuse, which is sensitive to PNS and progestogen milieu. This review explores the notion that allopregnanolone may effect, or be influenced by, PNS, with consequences for neurodevelopmental-, neuropsychiatric-, and/or neurodegenerative- relevant processes, such as addiction.

Discovery of early life stress interacting and sex‐specific quantitative trait loci impacting cocaine responsiveness

“…Collectively, these results indicate that there are probably genetic variants that interact with PNS to augment these traits while other variants interact with PNS to suppress these traits. Moreover, sex appears to be an important moderator of PNS effects, with males demonstrating higher sensitivity to the effects of PNS on many traits, which is generally consistent with findings from experiments using outbred rodent species (Bale, ; Frye et al, ; Weinstock, ).…”

“…Identification of these variants will enable the discovery of genes that interact with early life stress to moderate risk of cocaine addiction. In addition, many effects of PNS appear to be sex‐dependent (Bale, ; Frye, Paris, Osborne, Campbell, & Kippin, ; Weinstock, ) necessitating investigation of the potential sex specificity of gene by environment interactions that affect cocaine responsiveness.…”

Remodeling of axo-spinous synapses in the pathophysiology and treatment of depression

“…Exposure to stress during the perinatal period, either in utero or the early postnatal period, also impacts brain physiology and behavior of the newborn (Frye et al, 2011, Dunkel Schetter and Tanner, 2012). Stress experienced by the mother during pregnancy affects the development of brain circuitry in the progeny and increases the risk of neuropsychiatric disorders, such as schizophrenia, autism, anxiety and depression (Bertram and Hanson, 2002, Huizink et al, 2004, King, 2011).…”

Physiological Corticosterone Attenuates gp120-Mediated Microglial Activation and Is Associated with Reduced Anxiety-Like Behavior in gp120-Expressing Mice

“…One such neurocircuit that may be impaired by gp120 involves the hypothalamic-pituitary-adrenal (HPA) stress axis. The HPA stress axis is activated by psychological, physical, and immune challenges [ 13 , 14 ] and is characterized by corticotrophin releasing hormone secretion from the hypothalamus to the anterior pituitary, which thereby secretes adrenocorticotropic hormone (ACTH) to promote glucocorticoid synthesis from the adrenals. This neuroendocrine signaling is tightly regulated, with glucocorticoids acting to attenuate their own production in a negative feedback loop.…”