Stress and gonadal steroid influences on alcohol drinking and withdrawal, with focus on animal models in females - PubMed (original) (raw)

Review

Stress and gonadal steroid influences on alcohol drinking and withdrawal, with focus on animal models in females

Deborah A Finn. Front Neuroendocrinol. 2023 Oct.

Abstract

Sexually dimorphic effects of alcohol, following binge drinking, chronic intoxication, and withdrawal, are documented at the level of the transcriptome and in behavioral and physiological responses. The purpose of the current review is to update and to expand upon contributions of the endocrine system to alcohol drinking and withdrawal in females, with a focus on animal models. Steroids important in the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes, the reciprocal interactions between these axes, the effects of chronic alcohol use on steroid levels, and the genomic and rapid membrane-associated effects of steroids and neurosteroids in models of alcohol drinking and withdrawal are described. Importantly, comparison between males and females highlight some divergent effects of sex- and stress-steroids on alcohol drinking- and withdrawal-related behaviors, and the distinct differences in response emphasize the importance of considering sex in the development of novel pharmacotherapies for the treatment of alcohol use disorder.

Keywords: Androgen; Estrogen; Ethanol; Glucocorticoid; Neurosteroid; Progesterone; Stress.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.. Simplified depiction of the reciprocal interactions between the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes.

Dashed lines with block symbols illustrate inhibitory or negative feedback effects, whereas solid lines with arrows show facilitatory or positive feedback effects. Steroid feedback within each axis and between the axes are shown. Examples of regulatory centers that also influence activity of the HPA axis (left) and HPG axis (right) are shown. GABAergic projections from peri-PVH and noradrenergic and adrenergic inputs from brainstem neurons modulate activity in PVH and the HPA axis response. For the HPG axis, release of kisspeptin regulates GnRH activity. See text for details. Note: ACTH, adrenocorticotropic hormone; CORT; corticosterone in rodents, cortisol in humans and primates; CRF, corticotropin releasing factor; E, estrogen; EPI, epinephrine; FSH, follicle stimulating hormone; GABA, γ-aminobutyric acid; GnRH, gonadotropin releasing hormone; LH, luteinizing hormone; NE, norepinephrine; P, progesterone; POA, preoptic area; PVH, paraventricular nucleus of the hypothalamus; T, testosterone. Source: Modified from a figure by Finn, 2020 and Oyola & Handa, 2017.

Figure 2.. Overlap in the distribution of gonadal and adrenal steroid receptors within select brain regions that provide inputs to paraventricular nucleus of the hypothalamus (PVH) and peri-PVH.

This simplified circuitry shows GABAergic (red), glutamatergic (green) and dopaminergic (blue) projections within brain regions that have direct inputs to PVH or indirect inputs to PVH via an inhibitory GABAergic projection from peri-PVH. Fluctuations in brain steroid levels, derived from the circulation or from de novo synthesis, act on their respective receptors and exert genomic actions via nuclear receptors or rapid actions via membrane receptors or interactions with neurotransmitter receptors. Gonadal and adrenal steroid levels, in conjunction with the expression of gonadal steroid receptors for estrogen (ERα, ERβ), progesterone (PR), and androgen (AR) and expression of adrenal steroid receptors for glucocorticoids (MR, GR) within components of the hypothalamic, extrahypothalamic, and mesocorticolimbic circuitry, can influence output of the PVH. Thus, the brain regions involved and the overall influence on the output of the PVH depends on the stress, the effects of acute or chronic alcohol exposure, and the endogenous steroid levels and actions at their respective receptors. See text for details.Note: AR, androgen receptor; BNST, bed nucleus of the stria terminalis; ERα, estrogen receptor alpha; ERβ, estrogen receptor beta; GABA, γ-aminobutyric acid; GR, glucocorticoid receptor; mPFC, medial prefrontal cortex; MR, mineralocorticoid receptor; NAC, nucleus accumbens; PR, progesterone receptor (both isoforms); PVH, paraventricular nucleus of the hypothalamus; VTA, ventral tegmental area. Source: Modified from figures on circuitry (Finn, 2020; Finn & Jimenez, 2018; Handa & Weiser, 2014) and information on steroid receptor distribution (Brinton et al., 2008; Creutz & Kritzer, 2002; Handa & Weiser, 2014; Quigley et al., 2021; Schumacher et al., 2014; Tonn Eisinger et al., 2018; Willing & Wagner, 2016; Yoest et al., 2018).

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Stress and gonadal steroid influences on alcohol drinking and withdrawal, with focus on animal models in females - PubMed (original) (raw)