Stress and Gonadal Steroid Influences on Alcohol Drinking and Withdrawal, with Focus on Animal Models in Females (original) (raw)

. Author manuscript; available in PMC: 2024 Oct 1.

Published in final edited form as: Front Neuroendocrinol. 2023 Aug 8;71:101094. doi: 10.1016/j.yfrne.2023.101094

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: Estrogen, progesterone, androgen, glucocorticoid, ethanol, neurosteroid, stress

1. Introduction

The 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) integrates the two distinct DSM-IV disorders, alcohol abuse and alcohol dependence, into a single disorder that is called alcohol use disorder (AUD;NIAAA, 2021). According to the 2019 National Survey on Drug Use and Health, approximately 9 million men and 5.5 million women in the United States aged 12 and older have AUD, representing 6.8% of men and 3.9% of women in this age group (NIAAA, 2022a). Prevalence of binge drinking, defined by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) as a pattern of drinking that brings blood alcohol concentration to 80 mg/dl or higher (NIAAA, 2004), is reported in 29.7% of men and 22.2% of women aged 18 and older (NIAAA, 2022a). There are numerous negative health consequences in individuals with AUD, making alcohol the fourth leading preventable cause of death in the United States (NIAAA, 2022a). Notably, prevalence of binge drinking has been increasing in women, but not in men, that were between the ages of 31 – 65, when data were analyzed across studies during a 2000-2016 observation period (Grucza et al., 2018). In addition to this narrowing of the previous sex difference in rate of AUD (males > females), it should be considered that negative health consequences have been reported to be worse in females versus (vs) males with fewer years of heavy drinking (Erol & Karpyak, 2015 and references therein; NIAAA, 2022b; Wiren, 2013 and references therein). It is possible that telescoping, a phenomenon that refers to the amount of time between initial alcohol consumption and the onset of dependence, is more pronounced in women than in men (see Erol & Karpyak, 2015 and references therein). Overall, there are likely multiple reasons contributing to the above sex differences, including biological and psychological factors, with suggestions that the increased rate of AUD among women may reflect drinking to regulate negative affect and/or stress reactivity in females (Becker & Koob, 2016; Logrip et al., 2018; Peltier et al., 2019).

Function of the endocrine system is influenced by biological sex and is disrupted by acute and chronic alcohol exposure (Rachdaoui & Sarkar, 2017). Glands in the endocrine system secrete steroid hormones that influence and facilitate numerous physiological functions as well as the ability to respond to stress and to changes in the environment in order to maintain homeostasis (Oyola & Handa, 2017; Rachdaoui & Sarker, 2017). Sex steroids regulate sexual differentiation and secondary sex characteristics as well as sex differences in behavior via organizational and activational effects in the brain (Arnold & Gorski, 1984; Becker & Koob, 2016; Erol et al., 2019; McCarthy et al., 2012). Moreover, due to interactions and cross-talk between the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes, gonadal steroids influence the response to stress via the HPA axis, and elevated stress steroids negatively impact the reproductive or HPG axis (Oyola & Handa, 2017). Consequently, when considering the influence of sex and stress steroids on various effects of alcohol, it is important to bear in mind the interaction between the effects of alcohol exposure on the endocrine system as well as the reciprocal interaction between the HPA and HPG axes.

It is well documented that sex and stress hormones influence alcohol consumption, alcohol withdrawal, and behavior in models of addiction (Becker & Koob, 2016; Devaud et al., 2006; Erol et al., 2019; Flores-Bonilla & Richardson, 2020; Lenz et al., 2012; Logrip et al., 2018). The purpose of the current review is to update (Finn, 2020) and expand upon preclinical research related to the contributions of the endocrine system to alcohol drinking and withdrawal in females, with a focus on animal models. It will concentrate on steroids important in the HPG and HPA axes, the effects of alcohol exposure on steroid levels, and the influence of steroid administration on alcohol drinking, withdrawal, and other select addiction-related behaviors. Genomic effects and rapid membrane-associated effects of steroids and neurosteroids are considered. Comparisons of pertinent results between females and males highlight sex differences in steroid effects on alcohol drinking- and withdrawal-related behaviors. These comparisons and the sexually divergent responses emphasize the importance of considering sex in the development of novel pharmacotherapies for the treatment of AUD.

2. Overview of the HPG and HPA axes

Steroids in the HPG axis control reproductive behavior, and steroids in the HPA axis facilitate adaptation to stress. Synthesis and release of steroids in both axes are regulated by positive or negative feedback effects of steroids at different levels of each axis as well as by the reciprocal interactions between steroids in each axis (Figure 1).

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.

Responses to stress are mediated by the HPA axis and the sympathetic autonomic response. In general, short term activation of the HPA axis produces adaptive and beneficial effects, but chronic activation ultimately can lead to deleterious effects (McEwen et al., 2015). Briefly, stress stimulates neurons in the paraventricular nucleus of the hypothalamus (PVH) to facilitate the synthesis and release of corticotropin releasing factor (CRF) and arginine vasopressin (AVP) into the portal system. CRF triggers the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary by binding to CRF-receptor1 (CRF-R1) on corticotrophs. Then, ACTH stimulates the biosynthesis and release of glucocorticoids from the adrenal cortex (Handa & Weiser, 2014). Negative feedback of glucocorticoids (corticosterone in rodents, cortisol in humans and primates) at the level of the anterior pituitary and PVH inhibits CRF, AVP, and ACTH production and helps to maintain optimal glucocorticoid levels during basal conditions and in response to stress (Figure 1). Within the PVH, glucocorticoids also facilitate fast negative feedback via a membrane associated GR (mGR) and ultimate suppression of excitatory inputs to the CRF neurons (Evanson et al., 2010; Tasker et al., 2006). Neurons of the PVH also receive neuronal input from a variety of sources (e.g., γ-aminobutyric acid (GABA)ergic projections from peri-PVH; noradrenergic and adrenergic inputs from brainstem neurons) that integrate information and modulate the HPA axis response (see review by Handa & Weiser, 2014 for details).

The neuroendocrine axis that controls reproductive behavior and function is the HPG axis. Briefly, gonadotropin releasing hormone (GnRH) is released from hypothalamic nuclei (e.g., preoptic area, POA) in a regular pulsatile manner into the portal vasculature to stimulate the release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary. It is the stimulation of GnRH receptors on gonadotrophs in the anterior pituitary that controls the release of LH and FSH. Circulating LH and FSH act on the gonads to stimulate the production and release of estrogen and progesterone from the ovary and of testosterone from the testis (Handa & Weiser, 2014; Oyola & Handa, 2017;Rachdaoui & Sarkar, 2017). In males, LH stimulates the synthesis of testosterone, whereas FSH stimulates sperm cell maturation. In females, FSH stimulates follicle development in the ovary, and a coordinated action of FSH and LH in the ovary stimulates estrogen secretion. The rapid increase in estrogen triggers an LH surge, which stimulates progesterone release and ovulation. These overall effects of estrogen are similar across species, but phases of the 28 – 30 day menstrual cycle in humans and primates, which has distinct follicular and luteal phases, and the 4 – 5 day estrous cycle in rodents are not completely analogous. For instance, female rodents do not have a functional corpus luteum that releases high levels of estrogen and progesterone, with concomitant menstruation at the end of the luteal phase as steroid levels fall (see Table 1 in Finn, 2020). One upstream regulator of GnRH neurons is the hypothalamic peptide kisspeptin, which stimulates GnRH secretion (Oyola & Handa, 2017). Additionally, HPG axis function is regulated by steroid feedback at the level of the hypothalamus and anterior pituitary. Testosterone inhibits GnRH, LH, and FSH through negative feedback, whereas estradiol and progesterone exerts both negative (inhibitory) and positive (stimulatory) feedback actions, depending on the stage of the ovarian cycle (Figure 1).

Figure 1 also depicts the reciprocal interaction between the HPA and HPG axes, with steroids in the HPA axis contributing to the regulation of the HPG axis and vice versa (Finn, 2020; Oyola & Handa, 2017). For example, a chronic elevation in glucocorticoids suppresses HPG axis function via negative feedback of the HPG axis at the level of the hypothalamus, anterior pituitary, and gonads. Similarly, gonadal steroids influence HPA axis function, with effects of testosterone, progesterone, and estrogen at the level of the PVH and anterior pituitary (Handa & Weiser, 2014). For example, basal and stress-induced increases in glucocorticoids are higher in female than in male rodents. Evidence from studies utilizing gonadectomy (GDX) and hormone replacement suggest that testosterone exerts an inhibitory influence on HPA axis activity in male rodents, whereas estrogen primarily produces a facilitatory effect on HPA axis activity in female rodents. Some of the differing results for estrogen on HPA axis function may be due in part to the opposing actions of estrogen via binding to its two receptor subtypes (reviewed in Handa & Weiser, 2014). Nonetheless, female rodents have greater stress-induced release of CRF, ACTH, and corticosterone that reflects sex differences in the hypothalamus, anterior pituitary, and adrenal cortex, decreased negative feedback in females, and sex differences in CRF-R1 receptor signaling and trafficking in locus coeruleus (seeBangasser & Valentino, 2014 and references therein). Collectively, sex differences in components of the HPA axis, in conjunction with gonadal steroids, markedly influence basal and stress-induced changes in HPA axis function.

3. Steroid receptors and brain regions influencing PVH output

The PVH integrates information from several brain regions with fluctuations in steroid levels and activity at the pertinent steroid receptors to produce an appropriate response to stress or other physiological challenges. An important consideration is that steroids produce effects that are very rapid or that occur over hours to days via diverse mechanisms. First, steroid hormones bind to their classical intracellular receptors, which act as ligand-activated transcription factors to alter gene expression (Handa & Weiser, 2014) and produce long-lasting actions. For example, estrogens, such as 17β-estradiol, bind to two distinct receptor subtypes (estrogen receptor alpha, ERα; estrogen receptor beta, ERβ); progestins, such as progesterone and dihydroprogesterone, bind to two progesterone receptor (PR) isoforms (PR-A, PR-B); and androgens, such as testosterone and dihydrotestosterone, bind to androgen receptors (AR; Brinton et al., 2008; Handa & Weiser, 2014;Vasudevan & Pfaff, 2008). Glucocorticoids, such as corticosterone in rodents and cortisol in humans and monkeys, bind to mineralocorticoid receptors (MR, also type I) and glucocorticoid receptors (GR, also type II), with a higher affinity of endogenous glucocorticoids for MR vs GR (Handa & Weiser, 2014). These differences in affinity suggest that MR regulates HPA axis activity during the basal state and that GR regulates HPA axis activity following a stressor through negative feedback. Additionally, estrogen regulation of the HPA axis can occur at the level of the PVH, where ERβ is expressed and binds the CRF promoter to regulate transcription (Miller et al., 2004). Second, steroids produce rapid effects through their classical and non-classical receptors that are located in the cell membrane to influence second messenger pathways and ion channel function (Di et al., 2009; Foradori et al., 2008;Kelly & Rønnekleiv, 2015;Meitzen & Mermelstein, 2011; Vasudevan & Pfaff, 2008). For example, functional coupling between membrane-associated ER (both ERα and ERβ) and metabotropic glutamate receptors (Group I or Group II) can activate distinct signaling pathways independent of glutamate in several brain regions (Meitzen & Mermelstein, 2011). Glucocorticoids can bind to mGR in the PVH, causing the release of endocannabinoids and the suppression of glutamate release onto CRF-containing neurons via an action at the cannabinoid (CB1) receptor; this is an example of fast feedback inhibition of the HPA axis following the binding of glucocorticoids to mGR and initiating a nongenomic signaling mechanism (Evanson et al., 2010). Lastly, steroid derivatives can rapidly alter ion channel function via allosteric interactions with ligand-gated ion channels (Belelli & Lambert, 2005; Finn & Jimenez, 2018; Morrow et al., 2020; Paul & Purdy, 1992; Porcu et al., 2016; Zorumski et al., 2019). For instance, the progesterone derivative allopregnanolone (ALLO; 3α,5α-tetrahydroprogesterone) and the deoxycorticosterone (DOC) derivative THDOC (3α,5α-tetrahydrodeoxycorticosterone), are very potent positive allosteric modulators of γ-aminobutyric acidA(GABAA) receptors that rapidly alter neuronal inhibition. Rapid membrane actions gave rise to the terms “neuroactive steroids” and “neurosteroids” (see Figure 1 inFinn & Jimenez, 2018 for biosynthetic pathway of neurosteroids). Results showing that output of the PVH (e.g., CRF release) can be inhibited by physiological concentrations of ALLO via a potentiation of GABAA receptors (Gunn et al., 2011) represent a rapid neurosteroid-mediated mechanism to terminate the stress response. This finding is consistent with earlier work demonstrating that acute stressors increase ALLO and THDOC to levels that are physiologically active at GABAA receptors (see Barbaccia et al., 2001; Finn & Purdy, 2007) and that administration of ALLO prior to stress in male rats dampened activity of the HPA axis (Patchev et al., 1994, 1996). Thus, steroids and their derivatives can influence brain function and behavior via classic genomic actions and rapid membrane effects; these neuromodulatory systems can fine-tune the regulation of HPA axis function.

Recent work in male and female rats confirmed basal sex differences in CRF mRNA (female > male) and peptide (female < male) expression in the hypothalamus (Boero et al., 2021). There also were sex differences in the effect of ALLO administration (15 mg/kg, intraperitoneally, IP) on CRF mRNA or peptide levels in the hypothalamus, hippocampus, and central nucleus of the amygdala, with decreases observed only in males. In contrast, ALLO injection produced a similar increase in CRF peptide expression in the ventral tegmental area (VTA) in both males and females (Boero et al., 2021). Thus, ALLO regulation of CRF is sex and brain region dependent. A subsequent study determined that male and female rats were differentially responsive to the effect of ALLO injection (15 mg/kg, IP) prior to restraint stress or forced swim stress on regulation of the HPA axis. Exposure to both stressors significantly increased serum corticosterone levels in vehicle-treated rats. However, ALLO pretreatment decreased hypothalamic CRF and circulating corticosterone levels only in females after restraint stress, while it decreased hypothalamic CRF after forced swim stress in both sexes without altering corticosterone levels (Boero et al., 2022). Consequently, biological sex and type of stressor both influence the stress response and regulation of the HPA axis by neurosteroids.

Another consideration is that overlap in gonadal and adrenal steroid receptors within the hypothalamic (PVH) and extra-hypothalamic (e.g., bed nucleus of the stria terminalis (BNST), amygdala) stress circuitry as well as components of the mesocorticolimbic (e.g., medial prefrontal cortex (PFC), nucleus accumbens (NAC), VTA, hippocampus) circuitry also can affect output of the PVH (Figure 2). The simplified circuitry depicted in Figure 2 shows glutamatergic, GABAergic, and dopaminergic projections in brain regions important for responses to stress and for alcohol drinking- and withdrawal-related behaviors; these responses may be modulated by steroid actions at their receptors that are localized within the anatomical regions. As shown in Figure 2, many of the brain regions modulate HPA axis activity indirectly, by projecting to brain regions such as the BNST and peri-PVH that have direct GABAergic input to the PVH. In contrast, the amygdala exerts a facilitatory influence on the PVH via a glutamatergic projection. Overall, the brain regions involved and the overall influence on PVH output (e.g., the stress response) depends upon the stress, the various steroid levels and actions at their associated receptors (see reviews byHanda & Weiser, 2014; Oyola & Handa, 2017), and GABAAreceptor-active neurosteroid levels and actions at GABAA receptors (seeFinn & Jimenez, 2018; Morrow et al., 2020).

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).

Different modes of experimenter-administered alcohol (e.g., IP, intragastric, intracerebroventricular) activate the HPA axis at the level of the PVH (Lee et al., 2004; Ogilvie et al., 1997), with higher levels of ACTH and corticosterone after alcohol injection in female vs male rats due to an activational effect of estradiol (Ogilvie & Rivier, 1997). In contrast, evidence suggests that alcohol consumption either did not activate the HPA axis (Finn et al., 2004;Ogilvie et al., 1997), or produced a modest increase that was blunted in dependent animals (Richardson et al., 2008). With regard to alcohol’s effects on HPA axis function, it should be considered that the synaptic connections within the PVH are primarily GABAergic and glutamatergic (Miklós & Kovács, 2002; van den Pol et al., 1990). Consequently, glutamatergic projections that increase GABA release in the PVH or activation of the PVH by upstream GABAergic projection neurons both produce tonic inhibition of the PVH (Cullinan et al., 2008). Stress-induced elevations in GABAA receptor-active neurosteroids (Barbaccia et al., 2001; Finn & Purdy, 2007) represent another mechanism to inhibit CRF release and output of PVH neurons via potentiation of GABAA receptors (Gunn et al., 2011), although sex differences in responsivity of HPA axis components to regulation by ALLO exist (Boero et al., 2022). Another consideration is that alcohol-induced alterations in neurotransmission within the circuitry depicted in Figure 2 can be modulated by fluctuations in steroid and neurosteroid levels. For instance, estradiol and progesterone can rapidly affect dopamine signaling via actions at their steroid receptors; functional coupling between ER (both ERα and ERβ) and metabotropic glutamate receptors (Group I or Group II) can activate distinct signaling pathways; and neurosteroids can rapidly increase GABAAreceptor-mediated signaling (Belelli & Lambert, 2005; Creutz & Kritzer, 2002;Finn & Jimenez, 2018; Schumacher et al., 2014; Tonn Eisinger et al., 2018; Willing & Wagner, 2016; Yoest et al., 2018). Collectively, rapid steroid actions at their associated receptors or neurosteroid actions at GABAA receptors represent another mechanism to fine-tune central nervous system excitability that can be influenced by biological sex, alcohol, and stress.

4. Gonadal steroid and neurosteroid effects on alcohol drinking

There are many examples of sex differences in clinical and preclinical alcohol research, since alcohol exposure during the course of the lifespan can produce sexually dimorphic effects. The reader is referred to excellent reviews on sex differences in the developing brain in prenatal (Weinberg et al., 2008), adolescent (Dees et al., 2017; Kuhn, 2015; Spear, 2015; Witt, 2007), and adult (Becker & Koob, 2016; Rachdaoui & Sarkar, 2017) models of alcohol exposure. This section will focus on the effects of estrogen, progesterone, and their neuroactive metabolites during adulthood on alcohol drinking-related behaviors in females (some of the information was discussed in more detail in Finn, 2020). Sex differences in acquisition and maintenance of self-administration are well-documented, with females acquiring alcohol self-administration more rapidly and consuming higher doses of alcohol during maintenance phases than males (Becker & Hu, 2008; Becker & Koob, 2016;Carroll & Anker, 2010; Erol et al., 2019; Finn, 2020).

4.1. Gonadal steroids

Rodent drinking models confirm higher alcohol consumption in females vs males, due in part to a facilitatory effect of estrogen in females and an inhibitory effect of testosterone in males (reviewed in Becker & Koob, 2016; Guizzetti et al., 2016). Minimal effects of estrous cycle phase on the pattern of drinking were reported, with lower alcohol self-administration only observed in females during proestrus and estrus when their cycles had been synchronized (Roberts et al., 1998) and lower bout size during proestrus observed when microanalysis of alcohol drinking patterns were measured with lickometers (Ford et al., 2002a). However, the majority of evidence confirmed that phase of the estrous cycle did not significantly influence alcohol self-administration (Bertholomey & Torregrossa, 2019; Roberts et al., 1998), binge drinking (Satta et al., 2018), or the escalation in drinking in dependent animals (Priddy et al., 2017).

In a nonhuman primate model of alcohol self-administration, a recent study showed that normal menstrual cycle-related fluctuations in progesterone, especially during the late luteal phase, modulated alcohol drinking. Specifically, hormonal characterization of menstrual cycle phase in female rhesus monkeys across 15 months of alcohol drinking established that alcohol drinking was greater during the luteal vs follicular phase and highest in the late luteal phase when progesterone declined rapidly (Dozier et al., 2019). These results are consistent with clinical studies that reported an association in women between higher alcohol drinking during the late luteal phase and higher premenstrual distress and negative affective states (Becker & Koob, 2016; Hudson & Stamp, 2011). Taken in conjunction with results in female rodents, there is stronger evidence that normal gonadal steroid fluctuations during the menstrual cycle, but not during the estrous cycle, influence alcohol drinking. These differences likely reflect the distinct hormonal changes during the menstrual vs estrous cycle, where there is no equivalent luteal phase in rodents.

Several strategies have been used in rodents to confirm that the gonadal steroid environment contributes to sex differences in models of alcohol drinking behavior. Studies using the four core genotype (FCG) mouse model allow for determining whether sex differences in a phenotype, such as alcohol drinking behavior, are due to gonadal steroids or sex chromosomes or both (Arnold, 2020; Arnold & Chen, 2009). In this model, the sex determining gene (SRY) is translocated from the Y chromosome to an autosome, resulting in four different progeny in which gonadal sex (testes or _Sry_+ vs ovaries or_Sry_−) and sex complement (XX vs XY) are independent: XXF (XX gonadal females, _Sry_−), XXM (XX gonadal males,Sry+), XYF (XY gonadal females,_Sry_−), and XYM (XY gonadal males,Sry+). Use of the FCG model determined that gonadal females self-administered more alcohol than gonadal males, independent of sex chromosome complement (Barker et al., 2010). Similarly, 24 hr alcohol consumption was greater in gonadal females vs gonadal males (Sneddon et al., 2022), whereas binge alcohol consumption was higher in XY vs XX gonadal males (Sneddon et al., 2023). In contrast, habitual responding for alcohol reinforcement was mediated by sex chromosome complement independent of gonadal phenotype, with only XY mice responding in a habitual manner (Barker et al., 2010). Following instrumental training, chromosomal male (XY) mice were not sensitive to devaluation of the alcohol reinforcer by a conditioned taste aversion procedure, as the mice continued responding for an alcohol reinforcer at levels comparable to those before alcohol devaluation. Sex chromosome complement also contributed to the escalation in alcohol consumption following repeated deprivations, with XX chromosomes contributing to the alcohol deprivation effect (Sneddon et al., 2022). These different results between studies may reflect the different drinking paradigms utilized, and they also suggest that aspects of alcohol drinking behavior may be regulated by both gonadal hormones and sex chromosomes.

Studies utilizing GDX and hormone replacement found that the significant decrease in alcohol drinking in female GDX rats, and the significant decrease in binge drinking in female GDX mice, were restored to levels observed in intact animals following replacement with estradiol (Ford et al., 2002b, 2004;Satta et al., 2018). Similarly, GDX in male and female rats produced shifts in operant alcohol self-administration toward the opposite sex pattern (i.e., ↓ in females, ↑ in males), but it did not eliminate the sex difference as alcohol self-administration remained higher in GDX females vs GDX males (Bertholomey & Torregrossa, 2019). Additionally, the GDX-induced changes were reversed following steroid hormone replacement. That is, estradiol replacement in GDX females significantly increased alcohol self-administration, and testosterone replacement in GDX males significantly decreased alcohol self-administration (Bertholomey & Torregrossa, 2019). However, it should be noted that the suppressive effect of testosterone on alcohol drinking in rodent males contrasts with the fairly consistent clinical reports of a positive association between blood or salivary testosterone levels and alcohol drinking in adolescent and adult human males (see review by Erol et al., 2019). These different conclusions regarding the relationship between testosterone levels and alcohol consumption may reflect distinct strategies employed, with association studies in humans vs experimental manipulations to determine causal relationships in animals. Additionally, the focus of most studies on a particular hormone restricts the ability to consider circumstances that may reflect a complex interaction between multiple hormone levels. As suggested byErol et al. (2019), the balance between all gonadal steroids, which are present in both sexes but at different levels, and the hormones that regulate them (e.g., FSH, LH), may be important for determining sex-specific effects on alcohol drinking behavior.

Studies with conditioned place preference (CPP) as a measure of alcohol reward determined that intact but not GDX female rats exhibited CPP to an intermediate alcohol dose (Torres et al., 2014). Subsequent studies in GDX female mice determined that 17β-estradiol, as well as co-administration of agonists for both ERα and ERβ, facilitated alcohol-induced CPP (Hilderbrand & Lasek, 2018).

It is possible that the rapid ability of estradiol to enhance dopaminergic signaling (see review by Yoest et al., 2018) contributes to the above mentioned facilitatory effect of estradiol on alcohol drinking and CPP in GDX female rodents. For example, a low dose of alcohol (0.5 g/kg) enhanced extracellular dopamine levels in the PFC of female rats only during estrus (not during diestrus or proestrus), and this effect was eliminated by GDX and restored by estradiol treatment (Dazzi et al., 2007). An action of estradiol on membrane localized ERα and ERβ that are functionally coupled to metabotropic glutamate receptors is proposed to underlie the rapid enhancing effect of estradiol on dopaminergic signaling in females (Tonn Eisinger et al., 2018; Yoest et al., 2018). Collectively, the results described in this section suggest that in addition to the contribution of activational effects of gonadal steroids on alcohol drinking in males and females, permanent factors such as sex chromosomes and/or the organizational effects of gonadal steroids contribute to sex differences in alcohol drinking behaviors.

4.2. Neurosteroids

The neurosteroid ALLO is a potent positive allosteric modulator of GABAA receptors that is formed via the two-step reduction of progesterone (Belelli & Lambert, 2005; Finn & Jimenez, 2018;Giatti et al., 2020; Paul & Purdy, 1992; Porcu et al., 2016). In general, females have higher endogenous ALLO levels than males, and levels in females fluctuate across the estrous and menstrual cycle and increase during pregnancy in conjunction with the fluctuations in endogenous progesterone (Boero et al., 2021; Finn et al., 2004; Finn & Purdy, 2007;Genazzani et al., 1998; Paul & Purdy, 1992).

Several lines of evidence indicate that fluctuations in ALLO alter alcohol drinking and alcohol’s subjective effects. Many studies show that ALLO exerts a biphasic effect on alcohol drinking and operant self-administration following systemic and intracerebroventricular administration (i.e., ↑ with low physiological doses, ↓ with supra-physiological doses) in male rodents, but does not alter alcohol drinking in female mice (reviewed in Finn et al., 2010). Administration of pregnenolone, a precursor of progesterone and ALLO, produced a significant increase in cortical ALLO levels in the animals that were self-administering alcohol and a concomitant dose-dependent reduction in alcohol self-administration in male rats (Besheer et al., 2010). Overexpression of the biosynthetic enzyme cytochrome P450 side chain cleavage (P450scc) into the VTA of male rats, which facilitates the conversion of cholesterol to pregnenolone, significantly increased ALLO immunoreactivity in the VTA and decreased alcohol self-administration (Cook et al., 2014). Thus, administration of ALLO or manipulations that increase ALLO levels produced similar effects on alcohol drinking or self-administration, with the majority of studies being conducted in male rodents.

There also were sex differences in sensitivity to administration of the 5α-reductase inhibitor finasteride, which decreases endogenous GABAA receptor-active neurosteroids such as ALLO (Finn et al., 2006a), to decrease alcohol drinking behavior. Specifically, finasteride produced a rightward and downward shift in the acquisition and maintenance phases of alcohol drinking, with a higher dose required to suppress alcohol drinking behavior in female vs male mice (Ford et al., 2005, 2008a, 2008b). Collectively, manipulations that both increased and decreased ALLO levels decreased alcohol drinking and self-administration, raising the possibility that the suppression occurred via distinct effects on the regulatory processes that govern alcohol consumption (discussed in Finn et al., 2010).

Additional preclinical results suggest that ALLO and its 5β-isomer, pregnanolone, possess positive motivational effects as measured by CPP (Finn et al., 1997) and steroid preference drinking in male rodents (Finn et al., 2003; Sinnott et al., 2002), and by intravenous self-administration in one female and three male rhesus monkeys (Rowlett et al., 1999), with the highest self-administration of pregnanolone in the female monkey. Additionally, ALLO and pregnanolone possessed alcohol-like discriminative stimulus effects in male and female cynomolgus monkeys (reviewed in Grant et al., 2008), and female cynomolgus monkeys were more sensitive to the discriminative stimulus effects of alcohol as well as to the alcohol-like effects of ALLO during the luteal phase of the menstrual cycle when endogenous ALLO levels were highest (Grant et al., 1997). Overall, these results suggest that GABAergic neurosteroid levels may enhance the reinforcing effects of alcohol in male rodents and female monkeys, and that female monkeys may be sensitive to the modulatory effects of ALLO on alcohol drinking behavior. Consistent with this idea, results from the Dozier et al. (2019) study indicate that ALLO levels tended to be positively correlated with average alcohol intake in female rhesus monkeys (also see section 4.1 for relationship with progesterone levels).

The relative insensitivity of female mice to manipulations that alter endogenous neurosteroid levels and alcohol consumption was surprising, as it differed from the enhanced sensitivity to the anticonvulsant effect of the neurosteroids ALLO and THDOC exhibited by female rats during alcohol withdrawal (e.g., Devaud et al., 1995, 1998; also see section 5.2). Recent evidence in female alcohol preferring P rats also showed that administration of ALLO into the NAC core significantly increased ALLO immunoreactivity and reduced alcohol self-administration (Ornelas et al., 2023). Thus, female rats were sensitive to the effects of ALLO microinjection into the NAC core, but not into the VTA, on ethanol drinking behaviors. Based on evidence that local ALLO metabolism in hippocampal subregions significantly altered GABAA receptor-mediated inhibition (Belelli & Herd, 2003), it is possible that a sex difference in rapid ALLO metabolism in discrete brain regions contributes to the low sensitivity to ALLO’s modulatory effects on alcohol drinking in female mice and to the brain regional differences in sensitivity in female rats.

The synthetic ALLO analog ganaxolone (Carter et al., 1997) has a similar pharmacological profile to ALLO but an additional 3β-methyl group that protects the steroid from metabolic attack at the 3α-position and extends the half-life over that for ALLO. In male rodents, ganaxolone produced a biphasic effect on alcohol drinking and self-administration when administered systemically (Besheer et al., 2010; Ramaker et al., 2011, 2012) or bilaterally into the NAC shell (Ramaker et al., 2015). These effects were similar to those observed following ALLO administration. Preliminary results suggested that ganaxolone doses of 20 mg/kg in female mice (↓ 57%) and 10 mg/kg in male mice (↓ 53%) produced a comparable and significant suppression in alcohol drinking (see Figure 5 in Finn, 2020). Thus, there may be sex differences in sensitivity to the modulatory effect of ganaxolone on alcohol drinking in mice.

Ganaxolone is in phase 2 clinical trials for treatment of various disorders such as postpartum depression, treatment-resistant depression, post-traumatic stress disorder (PTSD), and epilepsy (http://clinicaltrials.gov). Another ALLO analog, brexanolone, has been approved for the treatment of postpartum depression (Edinoff et al., 2021; Powell et al., 2020), and it also is in clinical trials for treatment of PTSD, postpartum psychosis, perimenopausal depression, and epilepsy. A synthetic orally-active ALLO analog (SAGE-217) was recently reported to significantly reduce symptoms of depression in patients with major depressive disorder (Gunduz-Bruce et al., 2019). ALLO analogs or strategies to stabilize ALLO levels also are being examined in clinical trials for the treatment of various central nervous system disorders (reviewed in Belelli et al., 2020; Morrow et al., 2020; Reddy & Estes, 2016), and several clinical trials are at various stages in the examination of the effects of pregnenolone, allopregnanolone, and brexanolone on aspects of AUD. Thus, targeting neurosteroid synthesis or use of neurosteroid analogs may represent innovative therapies for the treatment of AUD in males and females (also see Giatti et al., 2020;Morrow et al., 2020; Porcu et al., 2016).

5. Gonadal steroid and neurosteroid effects on alcohol withdrawal

The development of dependence following chronic alcohol exposure can be inferred from the symptoms of withdrawal; reflecting a rebound hyperexcitability of the central nervous system that occurs upon removal of alcohol. Consistent evidence documents that the effects of alcohol on GABAA receptor mediated inhibition, and the subsequent deficit in GABAergic transmission, contribute to the development of dependence and the expression of withdrawal (see Finn et al., 2010; Kumar et al., 2009; Morrow et al., 2020and references therein).

Sex differences in alcohol withdrawal severity have been well documented, as the results from clinical and preclinical studies provide fairly consistent evidence for fewer and less severe somatic withdrawal symptoms in females vs males (see reviews by Becker & Koob, 2016; Devaud et al., 2006; Finn et al., 2010 and references therein). Elevated negative affect during withdrawal also has been reported to be higher in male vs female rodents, whereas some clinical studies report the opposite, with greater sensitivity to elevated negative affect during withdrawal in female vs male humans (see Becker & Koob, 2016; Bloch et al., 2022; Flores-Bonilla & Richardson, 2020 and references therein). It should be noted, however, that the expression of negative affective behavior often differs between male and female rodents for various behavioral tasks, which can complicate interpretation of a negative affective behavior construct in female vs male mice (see Bloch et al., 2022 and references therein). Thus, this section will describe evidence for the modulatory effects of gonadal steroids and neurosteroids on somatic symptoms of alcohol withdrawal severity, and how the hormonal milieu may contribute to sex differences in alcohol withdrawal severity.

5.1. Gonadal steroids

Different measures of convulsive activity during alcohol withdrawal revealed a faster recovery from withdrawal-induced convulsive activity in female vs male rats (Alele and Devaud, 2007;Devaud and Chadda, 2001) and the lack of a sensitized increase in convulsive activity with repeated withdrawals in female vs male mice (Veatch et al., 2007). The lower withdrawal severity in intact female rodents was not altered significantly by GDX, whereas GDX + 17β-estradiol produced a slight but non-significant decrease in convulsive activity in female mice and mixed results in female rats (Alele & Devaud, 2007; Devaud et al., 2000;Veatch et al., 2007). A significant reduction in somatic withdrawal signs also was reported in GDX female rats that received 17β-estradiol replacement vs GDX with no hormone replacement, but intact females were not tested (Jung et al., 2002). It is not known if the varying models of ethanol dependence induction (5 weeks alcohol liquid diet in the Jung study; 2 weeks alcohol liquid diet in the Devaud studies; repeated alcohol vapor exposure in the Veatch study) and subsequent neuroadaptations contributed to these differing effects of 17β-estradiol on withdrawal severity in GDX female rodents.

The above mentioned studies did not consider the potential contribution of progesterone on withdrawal severity. Administration of progesterone to male and female rodents exerts a potent anticonvulsant effect that is due to its metabolism to ALLO and enhancement of GABAA receptor mediated inhibition rather than via a PR-mediated effect (Reddy et al., 2004). It is possible that replacement with both estradiol and progesterone to GDX females is necessary to replicate the lower somatic symptoms of withdrawal that are observed in intact females.

The adrenal cortex is another source of gonadal steroid synthesis, and removal of the adrenals (adrenalectomy, ADX) and GDX was required to increase alcohol withdrawal convulsive activity following a hypnotic alcohol dose in female mice (Gililland & Finn, 2007;Strong et al., 2009). In a subsequent study, replacement with progesterone restored the withdrawal profile in the female ADX+GDX mice to levels observed in SHAM (surgery but no organs removed) animals, and this reduction in alcohol withdrawal severity was due to progesterone’s metabolism to ALLO (Kaufman et al., 2010).

5.2. Neurosteroids

ALLO and pregnanolone (progesterone derivatives) as well as THDOC (DOC derivative) are potent positive allosteric modulators of GABAAreceptors (see Finn & Jimenez, 2018and references therein), and their anticonvulsant properties have been examined in several models of alcohol withdrawal. In the model of withdrawal following a high dose of alcohol mentioned above, the increase in alcohol withdrawal severity induced by ADX+GDX in female mice was reversed by steroid replacement with either progesterone or DOC. Steroid replacement was not effective when progesterone or DOC were co-administered with finasteride, a 5α-reductase inhibitor that blocks the metabolism of progesterone and DOC to their respective GABAA receptor active neurosteroid (Kaufman et al., 2010). These results suggest that manipulation of the neurosteroid environment can alter alcohol withdrawal severity (↓ neurosteroids, ↑ withdrawal; ↑ neurosteroids, ↓ withdrawal).

During withdrawal following various models of chronic alcohol exposure, female and male rodents with a mild to moderate withdrawal convulsive profile exhibited enhanced sensitivity to the anticonvulsant effect of the neurosteroids ALLO, pregnanolone, and THDOC as well as the synthetic neurosteroids alphaxalone and ganaxolone, when compared to sensitivity in the respective controls; sensitivity to the anticonvulsant effect during withdrawal was greater in female vs male rodents in some studies (Alele & Devaud, 2007; Beckley et al., 2008; Cagetti et al., 2004;Devaud et al., 1995, 1996, 1998;Finn et al., 2000; Nipper et al., 2019). In contrast, sensitivity to the anticonvulsant effect of ALLO and ganaxolone was reduced during alcohol withdrawal in female and male mice with a high withdrawal convulsive profile, when compared to the robust anticonvulsant effect in respective controls (Beckley et al., 2008; Finn et al., 2000, 2006b; Nipper et al., 2019). Despite lower efficacy, it is notable that ganaxolone exerted a significant anticonvulsant effect during withdrawal in mouse genotypes with high withdrawal (Nipper et al., 2019). Collectively, these preclinical results suggest that the synthetic neurosteroid ganaxolone may exert protection against a range in severity of alcohol withdrawal-induced convulsions.

6. Chronic alcohol effects on gonadal steroid and neurosteroid levels

6.1. Gonadal steroids

Alcohol abuse and AUD produce significant pathophysiological and steroid hormone disruptions in the endocrine system (reviewed in Rachdaoui & Sarkar, 2017). Fairly consistent evidence in male and female rodents and humans suggests that chronic alcohol exposure or chronic intoxication significantly increased estradiol levels and produced a slight or significant decrease in progesterone levels in both males and females. In contrast, testosterone levels were decreased in males and transiently increased in females. Use of chronic alcohol vapor exposure to induce dependence significantly increased testosterone levels in female mice and disrupted their estrous cycle (i.e., prolonged diestrus; Forquer et al., 2011). In contrast, other preclinical studies suggest that either six weeks of binge drinking in female rodents (Satta et al., 2018) or fifteen months of active drinking in female monkeys (Dozier et al., 2019) did not significantly alter the estrous or menstrual cycle length or phases, respectively. Fifteen months of active drinking also did not alter progesterone or estradiol levels in the female monkeys (Dozier et al., 2019), nor did approximately 1-2 months of high alcohol drinking alter estradiol levels in female mice (Devaud et al., 2020). It is possible that the method of chronic alcohol exposure and resultant blood alcohol concentrations, which are considerably higher with vapor exposure (e.g., 200 mg%) vs drinking models (e.g., 80-100 mg%), contribute to the differences between studies in terms of whether the estrous or menstrual cycle was disrupted by the model of chronic alcohol exposure. Nonetheless, in people with AUD, numerous deleterious effects of alcohol on the HPG axis and its steroids can be associated with deleterious effects on reproduction in both males and females (see Rachdaoui & Sarkar, 2017).

6.2. Neurosteroids

Animal models utilizing chronic alcohol drinking or vapor exposure have shown that chronic intoxication and withdrawal both produce significant alterations in neurosteroid levels and functional changes in GABAAreceptor properties that lead to a reduction in GABAergic inhibition (see Finn & Jimenez, 2018; Porcu & Morrow, 2014 and references therein). Data from studies in male rodents and monkeys have shown that withdrawal from chronic alcohol drinking and vapor exposure significantly decreased plasma ALLO levels. In small cohorts of male and females with AUD, there was a significant decrease in plasma or serum ALLO and THDOC levels during detoxification that corresponded to an increase in the subjective ratings of anxiety and depression during early withdrawal, when compared to control subjects (Hill et al., 2005; Romeo et al., 1996). In contrast, animal models of chronic alcohol drinking determined that plasma or serum ALLO levels were significantly decreased during withdrawal in male but not female monkeys (Beattie et al., 2017; Dozier et al., 2019) and mice (Devaud et al., 2020). Withdrawal from chronic alcohol vapor exposure also significantly decreased plasma ALLO levels in male mice at 8 hrs (Jensen et al., 2017; Snelling et al., 2014) and 48 hrs of withdrawal (Jensen et al., 2017). A comparison of the results in female humans vs monkeys and mice suggests that a longer history of alcohol drinking may be necessary to observe a suppression in serum or plasma ALLO during early withdrawal in females, as was observed in female humans with AUD. More preclinical research in females is necessary, but the available preclinical results suggest that females may be protected from a chronic alcohol-induced suppression in ALLO synthesis. Taken in conjunction with ALLO’s anticonvulsant, anxiolytic, and antidepressant properties (seeBelelli et al., 2020; Finn & Jimenez, 2018; Morrow et al., 2020), the potential ability of females to maintain endogenous ALLO levels following chronic alcohol exposure may contribute to a lower alcohol withdrawal phenotype.

An examination of brain regional changes in ALLO levels revealed that chronic alcohol exposure and withdrawal significantly decreased ALLO levels in the amygdala of male monkeys, and in the NAC, VTA, amygdala subregions, and medial PFC of male rodents, with divergent changes reported in hippocampal subregions in male rodents (reviewed in Finn & Jimenez, 2018). For example, different modes of alcohol vapor exposure produced decreases in ALLO levels in medial PFC at 8 hrs (Jensen et al., 2017) and 72 hrs (Maldonado-Devincci et al., 2014) of withdrawal. A persistent decrease in ALLO immunoreactivity during withdrawal was reported in the lateral amygdala and VTA at both 8 hr and 72 hr time points, whereas ALLO levels in the PVH and BNST were unaltered during withdrawal (Maldonado-Devincci et al., 2014). Interestingly, exposure to stress immediately upon withdrawal from vapor exposure significantly increased ALLO immunoreactivity in the lateral amygdala at 8 hrs and 72 hrs, while stress exposure alone significantly decreased ALLO immunoreactivity in the PVH at the 72 hr time point (Maldonado-Devincci et al., 2016). Thus, chronic alcohol exposure produces brain regional and time-dependent changes in ALLO levels during withdrawal and also may alter brain regional responses to stress. Although comparable data in female rodents and monkeys are not available, a history of alcohol drinking and exposure to intermittent stress significantly increased cortical and hippocampal protein levels of the neurosteroid biosynthetic enzyme cytochrome P450scc in female but not in male mice at 24 hrs of withdrawal, when compared to respective values in naïve mice (Devaud et al., 2020). Given that plasma ALLO levels were decreased only in male mice at 24 hrs of withdrawal in theDevaud et al. (2020) study, it is not known whether the upregulation of cytochrome P450scc in female mice would stabilize neurosteroid levels and afford protection from withdrawal symptoms.

It is notable however, that an examination of neurosteroid levels in postmortem brains from primarily male patients with AUD found significant increases in pregnenolone and dehydroepiandrosterone levels in several brain regions such as the NAC, anterior insula, hippocampus, anterior cingulate, and PFC, but not the amygdala, when compared to controls (Kärkkäinen et al., 2016). A subsequent study with equal representation of postmortem brains from males and females with AUD vs controls determined that ALLO immunoreactivity was significantly increased in the VTA and substantia nigra pars medialis (SNM) but not in the amygdala (Hasirci et al., 2017). The significant increase in ALLO immunoreactivity in the VTA was determined by the results in AUD males, as the increase in AUD females was not significant. For the SNM, ALLO levels were significantly higher only in AUD males vs controls. Collectively, the results suggest that there is independent and time-dependent adrenal vs brain regional regulation of neurosteroid synthesis following chronic alcohol exposure and withdrawal and that the pattern of changes can be significantly altered by concomitant stress exposure. A comparison of the different brain regional withdrawal-induced differences between studies with animal models vs humans with AUD also point to distinct differences in neurosteroid regulation that should be considered. Additional studies in females are necessary to evaluate time-dependent and brain-regional changes in neurosteroid levels during alcohol withdrawal and the influence of concurrent stress exposure.

7. Stress effects on alcohol drinking and alcohol seeking behaviors

7.1. Stress steroids

Stress is positively associated with alcohol drinking in individuals with AUD, and it is suggested that HPA axis dysfunction may represent a biomarker of both risk and relapse (Blaine & Sinha, 2017). There also are different sensitivities to alcohol and stress in males and females (reviewed in Becker & Koob, 2016; Logrip et al., 2018; Peltier et al., 2019and references therein) that produce sex differences in HPA axis responsivity following acute stress or acute alcohol intoxication (i.e., enhanced elevation in glucocorticoids in females vs males). Given that acute stress exposure and alcohol intoxication both activate the HPA axis, the reciprocal interactions between the HPA and HPG axes should be considered (Figure 1). Discussion of all studies is beyond the scope of this review, so the reader is referred to reviews for details (Bangasser & Valentino, 2014; Finn & Jimenez, 2018; Handa & Weiser, 2014; Logrip et al., 2018; Oyola & Handa, 2017).

There is conflicting evidence regarding the influence of sex and various stress models to enhance alcohol drinking in rodents (reviewed in Cozzoli et al., 2014; Finn, 2020; Logrip et al., 2018). In spite of this, a few results showing a sex difference in the relationship between corticosterone levels and alcohol drinking or alcohol seeking will be described. First, exposure to predator odor stress (PS), which is considered a traumatic stressor and used as a rodent model of PTSD (Albrechet-Souza & Gilpin, 2019; Carlson & Weiner, 2021; Cohen et al., 2014;Deslauriers et al., 2018; Dielenberg & McGregor, 2001), significantly increased alcohol drinking and self-administration in rodents (reviewed in Gilpin & Weiner, 2017), with some evidence for greater PS-enhanced drinking in female vs male rodents (Alavi et al., 2022; Cozzoli et al., 2014; Finn et al., 2018a; Ornelas et al., 2021). Important for a model of PTSD and AUD comorbidity, there is heterogeneity with regard to the change in drinking observed after PS exposure [cat, soiled cat litter, dirty rat bedding, bobcat urine, TMT (2,5-dihydro-2,4,5-trimethylthiazoline)], when the PS was administered after a period of baseline alcohol intake. For example, we found that intermittent PS exposure significantly increased alcohol drinking in 24% of male and 20% of female mice (Alavi et al., 2022). Other studies reported an increase in alcohol intake or self-administration after PS exposure in a subgroup of animals characterized as “Avoiders” of a PS-paired context (Edwards et al., 2013), as exhibiting a high anxiety “extreme behavioral response” (Manjoch et al., 2016), or as exhibiting active coping behaviors during PS exposure (Ornelas et al., 2021). Additionally, we observed that plasma corticosterone levels were significantly higher in female vs male mice following PS exposure when mice were naïve and also when mice had a history of alcohol drinking (Alavi et al., 2022;Cozzoli et al., 2014; Finn et al., 2018a), and there was a significant positive correlation between plasma corticosterone levels and alcohol intake on the first day post-PS exposure that was stronger in females (Cozzoli et al., 2014). Second, reinstatement of alcohol seeking was significantly higher in female vs male rats, and corticosterone and estradiol levels were significantly positively correlated with active lever presses during reinstatement tests only in females (Bertholomey et al., 2016). Third, in mice with a history of alcohol drinking and exposure to PS, the PS-induced increase in plasma corticosterone was significantly lower in male mice, and tended to be lower in female mice, vs respective naïve mice (Finn et al., 2018a). This result is consistent with evidence that alcohol dependence in male rodents (Richardson et al., 2008) and AUD in humans can lead to a dampened neuroendocrine state in terms of HPA axis responsivity (see review by Rachdaoui & Sarkar, 2017; Stephens & Wand, 2012 and references therein). Collectively, the results suggest that overlapping stress and gonadal steroids, as well as sex differences in HPA axis responsivity, contribute to sex differences in alcohol drinking and alcohol seeking behavior and the interaction with stress. With regard to animal models of stress and alcohol drinking or self-administration, it is important to consider heterogeneity in response to stress and to include studies in females.

Preclinical studies also demonstrate cellular and molecular sex differences in stress response systems (reviewed in Bangasser & Valentino, 2014; Handa & Weiser, 2014; Logrip et al., 2018; Oyola & Handa, 2017). Both the GR and CRF receptor 1 (CRF-R1) are being pursued as potential pharmacotherapies for AUD, but the preclinical data in support of these targets have been generated primarily in males (discussed in Egli, 2018). Recent work in male and female mice found that a history of alcohol drinking and intermittent PS exposure produced sexually divergent and brain regional differences in GR and CRF-R1 protein levels, with increased cortical GR levels and hippocampal CRF-R1 levels only in female mice in the first study (Finn et al., 2018a) and increased medial PFC levels of CRF-R1, CRF-R2, CRF-binding protein, and GR in female mice that exhibited PS-enhanced drinking in a subsequent study (Alavi et al., 2022). As reviewed by Bangasser & Valentino (2014), these findings may imply the existence of impaired glucocorticoid negative feedback via an inhibition of GR translocation and increased CRF-R1 signaling and decreased CRF-R1 internalization in female vs male rodents. With the acknowledgement that there are numerous sex differences from the molecular to systems level that can increase endocrine responses to stress and alcohol intoxication in females, the sex differences in CRF-R1 and GR levels suggest that sexually divergent mechanisms may contribute to HPA axis dysregulation following a history of alcohol drinking and repeated stress exposure. As a result, pharmacological strategies targeting the CRF-R1 and GR systems may be differentially effective in males vs females.

7.2. Neurosteroids

Research in animal models has shown that exposure to stress (e.g., Barbaccia et al., 2001) and acute alcohol intoxication (see Finn & Jimenez, 2018; Morrow et al., 2006 and references therein) significantly increase levels of GABAAreceptor-active neurosteroids. For example, exposure to various stressors significantly increased plasma ALLO levels in male and female mice that had been consuming alcohol for weeks (Cozzoli et al., 2014), whereas weeks of alcohol consumption without stress exposure significantly increased brain ALLO levels in male but not in female mice (Finn et al., 2004). It should be noted that species-specific differences are reported (Porcu et al., 2010; Porcu & Morrow, 2014), and that minimal results are available in females, making it difficult to draw conclusions in females from the majority of results in males.

Acute administration of alcohol exerts a steroidogenic effect in male rats, which was due in part to an increase in ACTH release and de novo synthesis of adrenal steroidogenic acute regulatory protein (Boyd et al., 2010a). This neurosteroidogenic effect of alcohol administration was blunted following chronic alcohol exposure and was rescued following ACTH administration (Boyd et al., 2010b). Comparable studies have not been conducted in female rats. However, it should be noted that administration of CRF or ACTH to stimulate adrenal cortex function in human females significantly increased serum ALLO, progesterone, and dehydroepiandrosterone levels (Genazzani et al., 1998). Additionally, binge alcohol intoxication significantly increased serum ALLO levels in male and female adolescent humans (Torres & Ortega, 2003, 2004), but consumption of low alcohol doses in male adult humans did not increase ALLO levels significantly (Porcu et al., 2010). Collectively, the limited data in females suggest that stress and activation of the HPA axis consistently increased neurosteroid levels. In contrast, acute alcohol consumption produced inconsistent effects that may reflect differences in the model employed, the doses of alcohol consumed (binge vs non-binge), or species-related differences. Additional studies in females are necessary to determine whether an alcohol-induced steroidogenic effect can exert a protective effect against further alcohol drinking, as has been proposed for males (seeFigure 2 in Morrow et al., 2006). Related to this point, administration of progesterone (to increase ALLO levels) decreased cue-induced craving and cortisol responses in small cohorts of male and female patients having comorbid AUD and cocaine use disorder (Fox et al., 2013). It is interesting that both male and female subjects with the highest ALLO levels after progesterone administration exhibited the greatest reductions in craving (Milivojevic et al., 2016). A more recent study in women and men with AUD that were undergoing acute alcohol withdrawal established that higher serum progesterone levels correlated significantly with lower craving in post-menopausal women (Weinland et al., 2021). Additionally, maximum craving was significantly higher and serum progesterone levels were significantly lower in postmenopausal vs premenopausal women with AUD (Weinland et al., 2021). These studies confirm a negative correlation between serum progesterone levels and craving. Consequently, it is possible that strategies to enhance levels of GABAA receptor-active neurosteroids such as ALLO may be efficacious at reducing aspects of AUD in men and women (see Blaine & Sinha, 2017; Logrip et al., 2018; Morrow et al., 2020).

8. Summary and Conclusions

The current review considered the contribution of the endocrine system to alcohol drinking- and withdrawal-related behaviors in females, with a focus on the HPG and HPA axes. Results from animal models relevant to these two aspects of the addiction cycle (Becker & Koob, 2016;Flores-Bonilla & Richardson, 2020), which encompass aspects of positive reinforcement during the early stage of the addiction cycle and of negative reinforcement following chronic alcohol exposure and withdrawal, were described. In general, female rodents consume higher alcohol doses than male rodents in various models of consumption and self-administration, whereas withdrawal-induced convulsive activity is lower in females vs males. The hormonal milieu may contribute to these sex differences in alcohol drinking behaviors, as many differences were reduced by GDX (but not eliminated) and rescued by steroid replacement. However, sex chromosome complement contributed to habitual responding for alcohol and to the alcohol deprivation effect. Thus, aspects of alcohol-motivated behavior (e.g., alcohol drinking and self-administration) may be regulated by both gonadal steroids and sex chromosomes. With regard to alcohol withdrawal, GDX exerted minimal effects on withdrawal severity and did not eliminate the sex difference. Additional studies are necessary to determine whether organizational (permanent) and/or activation (transient) effects of gonadal steroids contribute to the sex difference in alcohol withdrawal severity. While the review discussed sex differences in somatic symptoms of alcohol withdrawal severity, steroid contributions to the various domains of alcohol withdrawal (e.g., affective, somatic) likely differ and should be investigated.

The reciprocal interactions between the HPG and HPA axes confirm that gonadal steroids influence the stress response and that elevated glucocorticoids suppress HPG axis function (Figure 1). There also are facilitatory and inhibitory feedback mechanisms within and between the HPA and HPG axes, and regulation of these axes by steroid hormones and their derivatives (e.g., neurosteroids) involves a combination of classic genomic actions and rapid membrane effects at receptors that are localized within brain regions important for responses to stress and for alcohol drinking- and withdrawal-related behaviors (Figure 2). Notably, sex differences in regulation of the HPA axis by gonadal steroids and by GABAAreceptor-active neurosteroids may fine-tune central nervous system excitability differently in males and females. Biological sex also influences the effects of chronic alcohol consumption, intoxication, and withdrawal on gonadal and stress steroid levels and adaptation of the HPG and HPA axes, providing another level of complexity toward understanding the influence of gonadal and stress steroids on alcohol drinking- and withdrawal-related behaviors.

Related to steroid targets in the HPA axis, preclinical studies indicate that biological sex also influences the transcriptional response to alcohol (seeHitzemann et al., 2022 and references therein), especially in medial PFC during the chronic intoxication and withdrawal stages of the addiction cycle (see Wilhelm et al., 2014 and references therein). A follow-up study determined that male and female mice exhibited similar increases in plasma corticosterone levels during alcohol withdrawal, but a dimorphic regulation of many corticosterone-responsive genes in medial PFC that involved a skew toward upregulation of several glucocorticoid target genes in females vs males (Wilhelm et al., 2015). The transcriptional response to repeated binge alcohol drinking in male and female mice also was influenced strongly by sex, with opposite regulation of genes in the NAC and distinct changes in signaling cascades and pathways, one of which was the CRF pathway (Finn et al., 2018b). These results suggest that therapeutic targets may be distinct between males and females and also at each stage of the addiction cycle, providing support for the idea that successful treatment may require an individualized approach.

Drugs targeting the GR and CRF-R1 are being pursued as potential treatments for aspects of AUD. However, the majority of these studies tested the drugs for their effects on alcohol drinking or alcohol seeking behavior in males, while a few clinical studies were underpowered to examine for sex effects. Regardless, it should be noted that despite promising preclinical data indicating that CRF-R1 antagonists effectively reduce the escalation in alcohol drinking in dependent male rodents, the compounds were not efficacious in clinical studies (discussed in Spierling & Zorrilla, 2017). The authors suggested that CRF-R1 antagonists may be effective in patients who show high activity in the CRF-R1 system. With this in mind, PS-enhanced drinking upregulated CRF-R1 in female vs male medial PFC and hippocampus (Alavi et al., 2022; Finn et al., 2018a). Taken in conjunction with evidence for increased CRF-R1 signaling and decreased CRF-R1 internalization in females vs males (Bangasser & Valentino, 2014), females may be more sensitive to repeated activation of the stress response via CRF mechanisms than males. However, the CRF-R1 antagonist verucerfont reduced HPA responsivity without altering measures of alcohol craving or the trait anxiety score in females with AUD and a comorbid anxiety disorder (Schwandt et al., 2016). Additional studies are necessary to determine whether verucerfont would reduce measures of alcohol drinking in females with comorbid anxiety and AUD.

Alterations in HPA axis regulation are associated with AUD, but the nature of this dysregulation may vary with the stage of alcohol dependence, and the majority of these studies have been conducted in males with AUD (Stephens & Wand, 2012). It has been hypothesized that neuroadaptations in glucocorticoid signaling in hypothalamic (e.g., PVH) and extra-hypothalamic (PFC and central nucleus of the amygdala) regions contribute to the transition from recreational drinking to alcohol dependence and AUD (Edwards et al., 2015). The induction of dependence in male rats also produced a dampened neuroendocrine state, with a blunting in the HPA axis response to alcohol that was most pronounced in the dependent animals with the highest alcohol self-administration (~ 1 mg/kg/30 min session; Richardson et al., 2008). Although similar studies have not been conducted in female rodents, a history of alcohol drinking and intermittent PS significantly increased GR levels in medial PFC of female but not male mice (Alavi et al., 2022; Finn et al., 2018a). Taken in conjunction with the reported sex differences in glucocorticoid signaling in dependent female vs male mice during early withdrawal (Wilhelm et al., 2015), it is likely that females would respond to drugs targeting the GR.

With regard to GR antagonists, the mixed GR and PR antagonist mifepristone significantly reduced measures of alcohol craving and alcohol consumption in patients with AUD that were predominantly male (82% in mifepristone treatment group) and significantly decreased alcohol self-administration in male dependent rats (no significant effect in non-dependent rats; Vendruscolo et al., 2015). More recent studies determined that mifepristone significantly decreased alcohol self-administration in Wistar rats (Benvenuti et al., 2021) and significantly decreased binge drinking in mice (Savarese et al., 2020), with a similar dose-dependent suppression in self-administration and binge drinking in the male and female rodents. Despite similar sensitivity between male and female rodents, it should be considered that mifepristone (also known as RU-486) is used in females to terminate pregnancy, due to its PR antagonism. So it is possible that use of mifepristone in females might be confounded by its mixed pharmacological properties, with the PR antagonism producing more serious side effects in females vs males. Studies with a more selective GR antagonist determined that CORT113176 significantly decreased binge drinking in mice selectively bred for a high binge drinking phenotype but not in mice with a low drinking phenotype; additionally, females were more sensitive than males to this suppressive effect on binge drinking (Savarese et al., 2020). CORT113176 also significantly decreased alcohol self-administration in male and female Wistar rats and in female Marchigian Sardinian alcohol-preferring rats (Benvenuti et al., 2021). Taken together, it is possible that pharmacological strategies targeting the CRF-R1 and GR systems may be differentially effective in females vs males and that new strategies targeting these systems could have greater specificity for females (discussed in Bangasser & Valentino, 2014).

Tactics focusing on GABAA receptor-active neurosteroids or their biosynthesis may represent an effective therapeutic strategy to treat symptoms of AUD in males and females. As recently reviewed, enhancing GABAergic inhibition by neurosteroids may restore the deficits in GABAergic transmission and/or hyperactivity of the HPA axis and extrahypothalamic CRF stress circuitry that occurs following excessive and chronic alcohol drinking (see review by Morrow et al., 2020 and references therein). Preclinical models provide evidence that chronic alcohol drinking or the induction of dependence in females did not decrease ALLO levels significantly, as was seen in males. These results suggest that the ability of females to maintain endogenous GABAergic neurosteroid levels following chronic alcohol exposure may contribute to their lower alcohol withdrawal phenotype. And, based on reports that women are more likely to drink to regulate negative affect and stress reactivity (Peltier et al., 2019), a strategy to enhance neurosteroid synthesis may exert a protective effect against further alcohol drinking in females, as has been proposed for males (Morrow et al., 2006). Neurosteroid analogs with a longer half-life than allopregnanolone show promise as another effective approach. Preclinical models of alcohol drinking, self-administration, and withdrawal convulsive activity document that ganaxolone significantly suppressed alcohol drinking and withdrawal in male and female rodents. Taken in conjunction with existing clinical trials examining the effects of neurosteroids on aspects of AUD, neurosteroid analogs may be effective at reducing alcohol drinking in patients with comorbid AUD and depression, with comorbid AUD and PTSD, or in patients with AUD that are drinking for negative reinforcement (i.e., to alleviate stress and negative affect). Finally, use of progesterone as a “prodrug” (to increase ALLO levels) significantly decreased craving in post-menopausal women with AUD and in men and women with comorbid AUD and cocaine use disorder. The results from these studies are consistent with a negative correlation between serum progesterone (and ALLO levels in one study) and craving. Collectively, strategies to utilize ALLO analogs with longer half-lives or to stabilize and/or enhance levels of GABAA receptor-active neurosteroids such as ALLO may represent new efficacious treatments for AUD in both males and females.

Taken together, it is important to increase our understanding of the neuroendocrine mechanisms underlying sex differences in all phases of the addiction cycle. Treatment strategies and their effectiveness should consider sex differences in the endogenous steroid and neurosteroid environments, the influence of chronic alcohol exposure, and sexually divergent downstream signaling mechanisms. These sex differences, in conjunction with variations in neurosteroid physiology, may contribute to individual differences in susceptibility to AUD and alcohol dependence as well as vulnerability to relapse and to negative health consequences of alcohol intake. As a result, a comprehensive approach toward studying AUD is necessary.

Highlights.

Sex and stress hormones influence alcohol drinking and withdrawal behaviors

GABAergic neurosteroids influence alcohol drinking and withdrawal behaviors

Sex differences in steroid effects on alcohol drinking and withdrawal behaviors

Sexually divergent effects of chronic alcohol exposure on steroid levels

Reciprocal interactions between HPA and HPG axes and interaction with alcohol

9. Funding

DAF is supported by VA Merit grant (BX002966) from the U.S. Department of Veterans Affairs, NIH R01 grant (AA028680) from the National Institute on Alcohol Abuse and Alcoholism, and by resources and facilities at the VA Portland Health Care System.

Footnotes

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Conflict of Interest Statement

There is no conflict of interest or competing financial interests to disclose.

Contribution to the Field Statement

A large body of evidence confirms sex differences in alcohol drinking behavior and in the severity of withdrawal. Research also corroborates that alcohol use and misuse in women is increasing, that the prevalence of alcohol use disorder (AUD) and binge drinking between the sexes has narrowed over the past 15+ years, and that women have a higher risk for some alcohol-related health problems. 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. Steroid hormones contribute to these differences, based on evidence from recent and historical data for gonadal and stress steroid effects on alcohol drinking- and withdrawal-related behaviors. Thus, 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 and 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 on 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. The distinct differences in response emphasize the importance of considering sex in the development of novel pharmacotherapies for the treatment of AUD.

12. Data Availability Statement

Published data mentioned in the review will be made available by the author to any qualified researcher.

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Data Availability Statement

Published data mentioned in the review will be made available by the author to any qualified researcher.