Sage Journals: Discover world-class research

Abstract

French

A significant amount of neurobiological research regarding the development of alcohol use disorders (AUDs) has focused on alcohol-related activation and long-term alterations in the mesocortical dopaminergic reward pathways. However, alcohol does not only interact with brain reward systems. Many of its acute and chronic effects may be related to allostatic adaptations in hypothalamic and extrahypothalamic stress regulation pathways. For example, acute binge intoxication is associated with hypothalamically driven increases in blood cortisol, norepinephrine, and sex steroid metabolite levels. This may contribute to the development of mesocortical sensitization to alcohol. Furthermore, chronic alcohol exposure is associated with systemic dysregulation of the hypothalamic pituitary adrenal axis, sympathetic adrenal medullary system, and sex steroid systems. This dysregulation appears to manifest as neuroendocrine tolerance. In this review, we first summarize the literature suggesting that alcohol-induced alterations in these hypothalamic systems influence craving and contribute to the development of AUDs. We note that for women, the effects of alcohol on these neuroendocrine stress regulation systems may be influenced by the rhythmic variations of hormones and steroids across the menstrual cycle. Second, we discuss how changes in these systems may indicate progression of AUDs and increased risk of relapse in both sexes. Specifically, neuroendocrine tolerance may contribute to mesocortical sensitization, which in turn may lead to decreased prefrontal inhibitory control of the dopaminergic reward and hypothalamic stress systems. Thus, pharmacological strategies that counteract alcohol-associated changes in hypothalamic and extrahypothalamic stress regulation pathways may slow the development and progression of AUDs.

Keywords

alcohol allostasis autonomic craving hypothalamic pituitary adrenal axis hypothalamic pituitary gonadal axis prefrontal cortex relapse

Recent statistics suggest that North Americans consume 50% more alcohol than the global average and engage in higher rates of detrimental binge drinking than residents of most European countries.¹ In addition, between 7% and 10% of North Americans suffer from current alcohol use disorders (AUDs).² Two core features of AUDs are craving and relapse. Craving can be described as a multifaceted phenomenon that incorporates the appetitive drive for reward, the need for reduction of associated physiological distress, and a compulsive motivational state characterized by strong intent with or without loss of control.³ Colloquially, craving is defined as an intense urge or abnormal yearning/longing⁴ and is often cited by those with AUDs as the reason for relapse.⁵ Relapse is defined as a return to any drinking (or, more significantly, a return to heavy drinking) after a defined period of abstinence.⁶ Although the importance of craving in the clinical experience of AUDs cannot be denied, its precise physiological and neurobiological underpinnings remain unclear. Historically, measures of craving have not been consistently associated with relapse in empirical studies.^7,8 For this reason, it was not included in Diagnostic and Statistical Manual of Mental Disorders (DSM) editions I to IV. However, it was added to DSM-5 as a symptom of substance use disorders,⁹ partially because with the new developments in methodology (such as ecological momentary assessments and refined laboratory and neuroimaging approaches), there is a clear link to craving, its neurobiological underpinnings, and it association with predicting future alcohol and drug use and relapse.¹⁰

Traditionally, the neurobiological literature on the development of AUDs has focused on the indirect and direct effects of alcohol on mesolimbic and mesocortical dopaminergic pathways.¹¹ In brief, the centrality of dopaminergic pathways in theories of AUD development is based, in part, on the following empirical evidence. Dopaminergic neurons in the ventral tegmental area (VTA) are directly activated by alcohol^12,13; these dopamine (DA) neurons project to the medium spiny neurons of the ventral striatum (VS), including those of the nucleus accumbens (NAcc) that express dopamine D2 receptors (D2Rs).¹⁴ Animal studies have shown that this sharp increase of DA in the VS underlies the initial positively reinforcing effects of alcohol: these phasic bursts of activity from VTA DA neurons in response to alcohol consumption increase the firing of afferents of the NAcc, which, in turn, is associated with the positive reinforcing effects of drugs of abuse.¹⁵ In addition, preclinical studies have shown that alcohol also binds at allosteric modulation sites of gamma amino butyric acid (GABA) receptors; this binding is associated with prolonged chloride channel openings and inhibition of postsynaptic cells.¹⁶ GABAergic inhibition within cognitive, emotion regulation, and motivational circuits throughout the cortex and midbrain have been linked to the sedative and negatively reinforcing effects of alcohol.¹⁷ Ultimately, the negatively reinforcing effects of alcohol consumption that are associated with GABAergic activity might also be encoded as positively valenced by influencing dopaminergic transmission in the VTA during rewarding processes.¹⁸

However, preclinical studies also indicate that alcohol directly affects the functioning of the hypothalamic pituitary adrenal (HPA) axis, the sympathetic adrenal medullary (SAM) system, and the hypothalamic pituitary gonadal (HPG) axis.^19
–21 These effects of alcohol on stress pathways are known to influence activity in dopaminergic pathways, but stress system activation may not only be important because of these indirect effects on DA release. In this review, we assess the literature suggesting that the fast and direct coactivation of the reward systems and core hypothalamic systems may be relevant in the increase in frequency and escalation of alcohol intake and thereby contribute to the development of AUDs. Taken together, the literature reviewed in this article suggests that 1) the experience of craving may be related to the development of mesocortical reward sensitization and co-occurring neuroendocrine tolerance in the HPA axis, SAM system, and HPG axis and 2) allostatic adaptations in these systems in response to binge and heavy drinking may contribute to a state of incentive sensitization and increased risk of relapse. Thus, medications that impede the development or progression of mesocortical sensitization and neuroendocrine tolerance may be useful in the treatment of AUDs.

Acute Alcohol Intake Activates Stress Regulation Systems

Preclinical studies suggest that several aspects of the physiological response to acute alcohol are linked to alcohol’s direct activation of neurosecretory cells of the hypothalamus.²² Intracerebroventricular infusion of alcohol activates neurons of the paraventricular nucleus (PVN) to produce corticotropin-releasing factor (CRF), or corticotropin-releasing hormone (CRH) in humans, which enters the portal blood vessels that link the hypothalamus to the anterior pituitary gland.²³ The CRF binds to corticotropin-releasing factor receptor 1 on pituitary corticotropes, inducing the release of adrenocorticotropic hormone (ACTH) into the circulation. ACTH then stimulates the adrenal cortex to synthesize and secrete glucocorticoids (corticosterone in rats, cortisol in humans). Animal models of acute intoxication indicate that this glucocorticoid release facilitates VS reward activation.²⁴ These stimulatory effects are potentially enhanced by the SAM system activation that results from alcohol’s effects on both the VS and PVN. Specifically, CRF release by the PVN induces excitatory signals to the sympathetic ganglia that synapse with the adrenal medulla.²⁵ This excitatory signal causes the release of acetylcholine in the adrenal medulla, which triggers the release of noradrenaline (NA) into the bloodstream.²⁶ NA increases blood pressure, triggers the release of glucose from energy stores, and increases blood flow to skeletal muscles. Thus, NA release contributes to the peripheral stimulatory effects of acute alcohol exposure.²⁷

In humans, acute alcohol intake has historically been associated with elevated ACTH, cortisol, and norepinephrine (NE) levels.^28

–32 However, these early studies involved administration of moderate to large doses of alcohol, with achieved blood alcohol content (BAC) at or above 0.08%. Other data suggest that ACTH, cortisol, and NE response to acute alcohol might depend on the dose, family history of alcoholism, and acute stress. For example, some data suggest that greater stimulatory effects of mild intoxication (BAC = 0.06%) are seen in individuals with a positive family history for alcoholism (FHP) than in those without FHP.³³ Other data suggest that mild alcohol intoxication (average BAC = 0.067%) does not raise cortisol or ACTH levels but can inhibit HPA axis response to cortisol administration.³⁴ Thus, the effect of acute alcohol on the HPA axis in healthy individuals might depend on acute stress levels. Participants with FHP without AUDs experience greater stress-related craving and consume more alcohol in response to stress than those without FHP.^35,36 Furthermore, 1 study showed that mild alcohol intoxication (average BAC = 0.066%) resulted in blunted HPA axis activity relative to placebo in healthy participants without FHP and there was no difference in HPA axis activity in healthy individuals with FHP.³⁷ This same study, however, showed an increased cortisol to ACTH ratio after alcohol consumption in all participants, suggesting that measures of adrenal sensitivity might be more indicative of HPA axis activation to acute alcohol than measures of cortisol or ACTH alone.

Finally, acute alcohol intake is associated with HPG axis activation in both animals and humans, although the mechanism by which it influences neurosecretory cells of the hypothalamus to release gonadotropin-releasing hormones is unclear.^38
–40 The presence of these hormones in the bloodstream influences the release of neuroactive steroids from the gonads into the circulation. Neuroactive steroids are metabolites of progesterone and testosterone and act on neural tissue directly.⁴¹ Neuroactive steroids are highly potent (at nanomolar concentrations), positive allosteric modulators of GABA_A receptor function.⁴² When bound simultaneously with GABA, neuroactive steroids increase the frequency of channel opening and the duration of the open state of the GABA_A receptor.⁴³ Because alcohol is also a positive allostatic modulator of GABA_A receptors, neuroactive steroids potentially contribute to the anxiolytic properties of alcohol.^44
–46

Binge Alcohol Consumption Sensitizes Reward Pathways by Altering Stress Regulation System Function

Binge drinking is defined by the National Institute on Alcohol Abuse and Alcoholism as the consumption of 5 or more standard drinks for male individuals and 4 or more for female individuals in 1 occasion.⁴⁷ Similarly, the World Health Organization defines binge drinking as the consumption of 6 or more standard drinks in 1 sitting.⁴⁸ With regular consumption of 4 to 6 drinks, alcohol-induced allostatic overload in mesocortical and mesolimbic pathways may be perpetuated by overactivation of the HPA axis, SAM system, and HPG axis in an attempt to adjust to the physiological load and facilitate neurobehavioral adaptations to adapt to a new set point. Specifically, glucocorticoids secreted via alcohol-induced hypothalamic activation modify reward-related behaviors by stimulating mesencephalic dopaminergic transmission and increasing NE levels in the prefrontal cortex (PFC).²⁴ Continued alcohol use seems to sensitize striatal reward function and may intensify craving.⁴⁹ NE, along with other neuronally derived catecholamines and glucocorticoids, may support mesocortical sensitization to alcohol cues by increasing the duration, magnitude, and probability of induction of long-term potentiation (LTP).⁵⁰ LTP is one synaptic restructuring mechanism that might underlie the association between alcohol intake and its reinforcing properties, both positive and negative.⁵¹ According to the allostatic model of addiction, a sustained increase in the tonic secretion of DA and NE may culminate in a failure to maintain homeostasis and may result in decreased functioning of the stress-related HPA and SAM systems.⁵² For example, blunted ACTH and cortisol response to pharmacological challenges have been demonstrated in frequent alcohol abusers.⁵³ Of note, the subjective experience of acute intoxication reported by binge drinkers matches predictions based on a state of mesocortical sensitization and neuroendocrine tolerance: binge drinkers report that 1 drink increases craving and stimulation, whereas light social drinkers report that 1 drink is anxiolytic and sedating.⁵⁴

Furthermore, severe acute intoxication, such as that associated with binge drinking, increases neuroactive steroid levels in the brain and periphery of animal models.^55,56 For example, intraperitoneal CRF and ACTH injections that mimic HPA activation in response to alcohol in rats result in increased brain and plasma levels of the neuroactive steroid allopregnanolone (ALLO), a derivative of progesterone.⁵⁷ In humans, the plasma concentration of ALLO is increased after severe intoxication,^58,59 and variation in genes that encode neuroactive steroid synthesis enzymes are associated with both the subjective alcohol effects of alcohol⁶⁰ and AUD diagnoses.⁶¹ Notably, gender differences in HPG axis activity may result in greater sensitization to the reinforcing effects of alcohol during different menstrual cycle phases.⁶² For women, the basal level of circulating neuroactive steroids varies by menstrual cycle phase. Basal circulating neuroactive steroid levels are less than 1 nM in women in the follicular phase, similar to basal levels in men.⁶³ However, basal levels increase as high as 4-fold in women during the luteal phase.⁶⁴ During the luteal phase then, the anxiolytic properties of acute alcohol intake may be heightened in women and learning of the negative reinforcing properties of alcohol may be enhanced.

It is important to note that frequent alcohol abusers and binge drinkers are often recruited from the college-age population, because binge drinking is an increasingly popular recreational activity for this age group.⁶⁵ However, most binge drinkers “mature out” of a pattern of frequent alcohol binges as they move through their 20s,⁶⁶ a fact that could potentially weaken theories regarding the role of physiological adapatation of hypothalamic systems in the transition from normative, context-driven binge drinking to sustained AUDs. Although adoption of adult social and occupational roles reduces this behavior for most young adults, a certain portion persist in frequent binge drinking. A recent longitudinal study suggested that those who persist in this behavior through their late 20s and early 30s show greater initial sensitivity to the stimulating effects of alcohol, accompanied by lower cortisol release and lower sensitivity to the sedative effects of alcohol than those who do not continue binge drinking.^67,68 Importantly, those who persist in binge drinking show this same physiological response to an alcohol challenge 6 years later at follow-up.⁶⁹ In this set of studies, one-third of the heavy-drinking participants met criteria for alcohol dependence at follow-up. Thus, current research suggests that the persistence of meoscortical sensitivity and a co-occurring low HPA axis repsonse to binge/heavy alcohol intake representative of neuroendocrine tolerance combined with neurobehavioral sensitization in mesocortical dopaminergic systems may be indicative of a transition between sucessful allostatic accomodation to binge drinking with a dominance of allostatic overload seen in severe AUDs.

After acute alcohol exposure that is limited in both dose and duration, the dopaminergic and hypothalamic systems are able to return to normal tonic functioning and maintain the ability to phasically respond to novel stimuli. This return to a basal set point occurs via allostatic processes. By definition, allostatic processes allow the brain and body to achieve physiological stability through challenges to homeostasis by altering cellular structure and function to establish a new physiological set point.⁷⁰ In the healthy basal state, the number and sensitivity of dopaminergic, GABAergic, and corticotropic receptors returns to preintoxication levels. However, binge/heavy and excessive alcohol consumption results in adaptations and wear and tear (allostatic overload) to the reward and neuroendocrine regulation circuits.⁵² In summary, adaptations in these stress system mechanisms, in addition to altered dopaminergic function, may represent the pathophysiology underlying the transition from controlled to compulsive alcohol seeking in humans.^10,71

Chronic, Heavy Alcohol Consumption Is Associated With Neuroendocrine Tolerance in Stress Regulation Systems

Chronic alcohol-related allostatic changes have also been documented in AUDs in addition to the altered stress responses to acute heavy alcohol intake. In a sample of chronic moderate to severe inpatient treatment–engaged, alcohol-dependent individuals who were abstinent for 4 weeks, we reported higher basal ACTH levels and blunted alcohol cue-induced ACTH and cortisol responses compared with healthy social drinkers.⁷² Furthermore, alcohol-dependent individuals with high fasting morning basal cortisol to ACTH ratios (which is a measure of sensitivity of the adrenal glands to release cortisol in response to the ACTH signal) were more likely to relapse after treatment discharge from inpatient treatment in a prospective assessment of relapse outcomes.⁷³ Results indicated that elevated morning cortisol to ACTH ratios more than doubled the risk of future relapse. Such basal HPA axis hyperreactivity is associated with blunted response to stress and alcohol cues and increased craving levels, which in turn, may result in high levels of alcohol intake possibly to physiologically normalize or activate the HPA axis.⁷³ This is consistent with other studies that have reported an association between blunted cortisol release in response to stress and alcohol cues during early abstinence and increased risk of relapse.⁷⁴ Early abstinence is also associated with a downregulation of both the dopaminergic tone in mesocortical circuits and decreased phasic release of DA in response to alcohol consumption.⁷⁵ It is important to note that decreased levels of striatal D2Rs persist in patients with AUDs at least for up to 4 months after alcohol detoxification.⁷⁶ These low DA levels are associated with relapse.⁷⁷ Clinically, this state of neuroendocrine and reward system tolerance may be linked to an unpleasant high arousal state with increased alcohol abstinence symptoms that is only partially mitigated by further alcohol consumption,⁷⁸ thereby continuing the cycle of alcohol intake and abstinence.

In conjunction with HPA axis dysregulation, sympathetic dominance may develop in AUDs.⁷⁹ Sympathetic dominance over central and peripheral processes may be both developed and perpetuated via elevations of central NE in the PFC and NA in the circulation.⁸⁰ First, chronic high levels of NE, acting at α1 receptors, are thought to induce sympathomimetic states associated with withdrawal.^81,82 Second, chronic α1 receptor stimulation in the PFC is known to impair attentional processes by attenuating salient “signals” and increasing irrelevant “noise.”⁸³ When the PFC cannot distinguish between relevant and irrelevant stimuli, mesolimbic brain regions may show greater bottom-up influence in behavior. Sustained increases in NE in extrahypothalamic regions and the PFC, therefore, decrease the ability of the prefrontal cortical pathways to appropriately inhibit habit-based responding to alcohol cues.⁸⁴ Increased NA in the circulation might further prime the brain to depend on instinctual and habit-based responding by keeping fight-or-flight bodily systems activated in the basal state. Chronic alcoholism is associated with impaired autonomic regulation characterized by high basal heart rate, reduced heart rate variability, and increased blood pressure.^85
–87 The development of this tonically physically aroused state may also adversely influence neural activity by blunting the ability of the HPA axis to respond to stress and future binge alcohol exposures.

The risk of relapse is also increased by HPG axis dysregulation. For example, the increase in neuroactive steroids that occurs during acute intoxication counteracts HPA axis activation, thereby contributing to the blunted response of the HPA axis to alcohol and stress seen in AUDs.⁸⁸ Furthermore, clinical studies have demonstrated that levels of neuroactive steroids increase during binge intoxication^58,59 and then decrease significantly during alcohol withdrawal.⁸⁹ With repeated cycles of binge intoxication and withdrawal, as is characteristic of AUDs, this neuroactive steroid response may become desensitized and its protective effects during acute intoxication may become diminished. This loss may worsen the basal state HPA and SAM hyperactivity seen in withdrawal and during early abstinence.

Furthermore, chronic alcohol exposure elevates estrogen in both men and women.⁹⁰ Estrogen is known to modulate DA activity in the striatum and NAcc and is associated with higher levels of cortisol, which in turn may increase vulnerability to relapse.^91,92 For women, alcohol-induced increases in estrogen levels are potentiated during the late luteal (premenstrual) menstrual cycle phase. Thus, the late luteal phase could be a phase of increased vulnerability to cue-related craving.⁹³ Female individuals with AUDs showed greater ACTH blunting after alcohol cue exposure compared with male individuals with similar AUD symptomatology.^94,95 This may represent an important risk factor for women with AUDs, in view of the fact that HPA axis hyporeactivity to alcohol consumption has been associated with greater craving and a return to early drinking in those with AUDs.^96,97 High estrogen levels might therefore contribute to the blunted hypothalamic response to alcohol and to basal state hyperactivity of the HPA and SAM. Collectively, chronic alcohol exposure related changes in the HPA axis, SAM system, and HPG axis result in increased neuronal signaling of glucocorticoids and catecholamines that interact to dysregulate the PFC,⁹⁸ the area of the brain responsible for inhibiting emotion- and habit-based responding to interoceptive and environmental alcohol cues.⁹⁹

Allostatic Overload Decreases Prefrontal Regulation of Stress Pathways

The PFC is critical for adaptive coping via executive control of behavior through higher-order functions such as planning, working memory, inhibition, and abstract reasoning.¹⁰⁰ AUDs are associated with stress-related decreased PFC function and deficits in behavioral flexibility, emotion regulation, and cognitive control.¹⁰¹ In healthy individuals, the PFC modulates alcohol cue responsivity and craving via its regulatory influences on the hypothalamic PVN and thus autonomic system activity.^102
–104 The PFC has also been shown to inhibit PVN activity via the GABAergic interneurons of the bed nucleus stria termanalis.¹⁰⁵ Its output could therefore decrease HPA and SAM responses to alcohol cues, including acute alcohol intake.¹⁰⁶ However, as noted earlier, alterations in the HPA axis, SAM system, and HPG axis interact to take the PFC “off-line” via sustained excess glucocorticoid and catecholamine release; these molecules modulate ionic regulation of microcircuits,¹⁰⁷ resulting in a failure to maintain homeostasis and a concomitant decrease in the function of normal reward and stress-related neurocircuitry.^52,108 Furthermore, chronic basal cortisol exposure maintains excitotoxic cascades that result in decreased dendritic length and decreased spine density of the dendrites in the PFC.¹⁰⁹ These structural changes may underlie PFC dysfunction that may manifest not only as reduced cognitive function basally but also as a loss of self-directed behavior that may be replaced by habit and sensory-driven automatic responding.¹¹⁰ Recent findings from our laboratory support this notion by documenting that disrupted PFC function in the neutral-relaxed state and in response to alcohol or stress cues is predictive of a shorter time to future relapse in abstinent, treatment-engaged, alcohol-dependent individuals.¹¹¹ Importantly, this disrupted PFC function appears to mediate the relationship between earlier reported adrenal sensitivity and future relapse risk (unpublished observation). The associated lack of top-down inhibition may result in increased craving and a resumption of drinking behavior in newly abstinent patients.¹¹² Resumed consumption of alcohol then worsens autonomic and HPA axis dysfunction, making the next recovery attempt more difficult.¹¹³

Future Research to Target Hypothalamic and Extrahypothalamic Stress Regulation Systems in Treatment of AUDs

In summary, this review suggests that alcohol-induced HPA, HPG, and SAM system dysfunction promotes and contributes to sensitized mesocortical dopaminergic reward circuits to influence craving and the development of AUDs. With chronic alcohol consumption, a decreased influence of prefrontal executive control over stress and reward systems may result in increased craving and a greater susceptibility to habit-based maladaptive coping (that is, relapse to drinking behavior).¹¹² Resumed consumption of alcohol may eventually lead to decreased reward functioning and neuroendocrine tolerance. The allostatic overload in these systems may weaken the regulatory influence of the PFC over hypothalamic and extrahypothalamic stress and reward circuits.¹¹³ Therefore, pharmacotherapies that stabilize PFC dysfunction directly or indirectly might be efficacious in the treatment of AUDs. Alternatively, medications that normalize HPA, HPG, and SAM axis functioning may also restore PFC functioning and prove of benefit in alcohol relapse prevention. One of the three currently approved medications for the treatment of AUDs, naltrexone, is thought to decrease craving and self-reported high by modulating opioid activity in dopaminergic reward pathways.¹¹⁴ However, these drug effects may also derive from naltrexone’s normalization of the HPA axis activity in the basal state and in response to acute alcohol.^115,116 Future research that tests the effects of drug treatments on alcohol-induced hypothalamic stress systems may clarify not only the interaction between naltrexone and the HPA axis but also the role of hypothalamic and extrahypothalamic stress regulation systems in the development and progression of AUDs.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Institutes of Health (NIH) Common Fund and NIH grants UL1-DE019586, R01-AA013892-11, T32 DA0022975 NISTP, and T32 DA007238-24.

References

Shield

Rylett

Gmel

. Global alcohol exposure estimates by country, territory and region for 2005—a contribution to the Comparative Risk Assessment for the 2010 Global Burden of Disease Study. Addiction. 2013;108(5):912–922.

Pearson

Janz

Ali

. Mental and substance use disorders in Canada. Statistics Canada. 2013;82-624(1925-6493):1–8.

Verheul

van den Brink

Geerlings

. A three-pathway psychobiological model of craving for alcohol. Alcohol Alcohol. 1999;34(2):197–222.

Merriam-Webster. Merriam-Webster’s collegiate dictionary, 11th ed. Springfield (MA): Merriwam-Webster; 2004.

Kvamme

Asplund

Bjerke

. Drinking resumption: problematic alcohol use relapse after rehabilitation. A phenomenological hermeneutical perspective. Scand J Caring Sci. 2015;29(4):716–723.

Becker

. Alcohol dependence, withdrawal, and relapse. In: Noronha

Cui

Harris

Crabbe

, editors. Neurobiology of Alcohol Dependence. San Diego (CA): Academic Press; 2014. p. 377–410.

Leggio

Ray

Kenna

. Blood glucose level, alcohol heavy drinking, and alcohol craving during treatment for alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) Study. Alcohol Clin Exp Res. 2009;33(9):1539–1544.

Cherpitel

Borges

. Performance of a craving criterion in DSM alcohol use disorders. J Stud Alcohol Drugs. 2010;71(5):674–684.

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington (VA): American Psychiatric Publishing; 2013.

10.

Sinha

. The clinical neurobiology of drug craving. Curr Opin Neurobiol. 2013;23(4):649–654.

11.

Nutt

Lingford-Hughes

Erritzoe

. The dopamine theory of addiction: 40 years of highs and lows. Nat Rev Neurosci. 2015;16(5):305–312.

12.

Rodd

Melendez

Bell

. Intracranial self-administration of ethanol within the ventral tegmental area of male Wistar rats: evidence for involvement of dopamine neurons. J Neurosci. 2004;24(5):1050–1057.

13.

Brodie

Pesold

Appel

. Ethanol directly excites dopaminergic ventral tegmental area reward neurons. Alcohol Clin Exp Res. 1999;23(11):1848–1852.

14.

Anzalone

Lizardi-Ortiz

Ramos

. Dual control of dopamine synthesis and release by presynaptic and postsynaptic dopamine D2 receptors. J Neurosci. 2012;32(26):9023–9034.

15.

Yorgason

Ferris

Steffensen

. Frequency-dependent effects of ethanol on dopamine release in the nucleus accumbens. Alcohol Clin Exp Res. 2014;38(2):438–47.

16.

Paul

. Alcohol-sensitive GABA receptors and alcohol antagonists. Proc Natl Acad Sci U S A. 2006;103(22):8307–8308.

17.

Kumar

Porcu

Werner

. The role of GABAA receptors in the acute and chronic effects of ethanol: a decade of progress. Psychopharmacology (Berl). 2009;205(4):529–564.

18.

Addolorato

Leggio

Hopf

. Novel therapeutic strategies for alcohol and drug addiction: focus on GABA, ion channels and transcranial magnetic stimulation. Neuropsychopharmacology. 2012;37(1):163–177.

19.

Stephens

MAC

McCaul

Wand

. The potential role of glucocorticoids and the HPA axis in alcohol dependence. In: Noronha

Cui

Harris

Crabbe

, editors. Neurobiology of Alcohol Dependence. San Diego (CA): Academic Press; 2014. p. 429–450.

20.

Boschloo

Vogelzangs

Licht

. Heavy alcohol use, rather than alcohol dependence, is associated with dysregulation of the hypothalamic–pituitary–adrenal axis and the autonomic nervous system. Drug Alcohol Depend. 2011;116(1):170–176.

21.

Rachdaoui

Sarkar

. Effects of alcohol on the endocrine system. Endocrinol Metab Clin North Am. 2013;42(3):593–615.

22.

Rivier

. Role of hypothalamic corticotropin-releasing factor in mediating alcohol-induced activation of the rat hypothalamic–pituitary–adrenal axis. Front Neuroendocrinol. 2014;35(2):221–233.

23.

Lee

Selvage

Hansen

. Site of action of acute alcohol administration in stimulating the rat hypothalamic-pituitary-adrenal axis: comparison between the effect of systemic and intracerebroventricular injection of this drug on pituitary and hypothalamic responses. Endocrinology. 2004;145(10):4470–4479.

24.

Piazza

Le Moal

. Glucocorticoids as a biological substrate of reward: physiological and pathophysiological implications. Brain Res Brain Res Rev. 1997;25(3):359–372.

25.

Randin

Vollenweider

Tappy

. Suppression of alcohol-induced hypertension by dexamethasone. New Engl J Med. 1995;332(26):1733–1738.

26.

Nunn

Womack

Dart

. Function and pharmacology of spinally-projecting sympathetic pre-autonomic neurones in the paraventricular nucleus of the hypothalamus. Curr Neuropharmacol. 2011;9(2):262–277.

27.

Ireland

Vandongen

Davidson

. Acute effects of moderate alcohol consumption on blood pressure and plasma catecholamines. Clin Sci (Lond). 1984;66(6):643–8.

28.

Wright

. Endocrine effects of alcohol. Clin Endocrinol Metab. 1978;7(2):351–367.

29.

Ehlers

Wall

Schuckit

. EEG spectral characteristics following ethanol administration in young men. Electroencephalogr Clin Neurophysiol. 1989;73(3):179–187.

30.

Frias

Rodriguez

Torres

. Effects of acute alcohol intoxication on pituitary-gonadal axis hormones, pituitary-adrenal axis hormones, β-endorphin and prolactin in human adolescents of both sexes. Life Sci. 2000;67(9):1081–1086.

31.

Howes

Reid

. Changes in plasma free 3, 4-dihydroxyphenylethylene glycol and noradrenaline levels after acute alcohol administration. Clin Sci (Lond). 1985;69(4):423–428.

32.

Borg

Kvande

Sedvall

. Central norepinephrine metabolism during alcohol intoxication in addicts and healthy volunteers. Science. 1981;213(4512):1135–1137.

33.

Söderpalm Gordh

Söderpalm

. Healthy subjects with a family history of alcoholism show increased stimulative subjective effects of alcohol. Alcohol Clin Exp Res. 2011;35(8):1426–1434.

34.

Waltman

Blevins

Jr Boyd

. The effects of mild ethanol intoxication on the hypothalamic-pituitary-adrenal axis in nonalcoholic men. J Clin Endocrinol Metab. 1993;77(2):518–522.

35.

Zimmermann

Spring

Kunz-Ebrecht

. Effect of ethanol on hypothalamic–pituitary–adrenal system response to psychosocial stress in sons of alcohol-dependent fathers. Neuropsychopharmacology. 2004;29(6):1156–1165.

36.

Gordh

Brkic

Söderpalm

. Stress and consumption of alcohol in humans with a type 1 family history of alcoholism in an experimental laboratory setting. Pharmacol Biochem Behav. 2011;99(4):696–703.

37.

Mick

Spring

Uhr

. Alcohol administration attenuates hypothalamic–pituitary–adrenal (HPA) activity in healthy men at low genetic risk for alcoholism, but not in high-risk subjects. Addict Biol. 2013;18(5):863–871.

38.

O’Dell

Alomary

Vallée

. Ethanol-induced increases in neuroactive steroids in the rat brain and plasma are absent in adrenalectomized and gonadectomized rats. Eur J Pharmacol. 2004;484(2-3):241–247.

39.

Khisti

Kumar

Morrow

. Ethanol rapidly induces steroidogenic acute regulatory protein expression and translocation in rat adrenal gland. Eur J Pharmacol. 2003;473(2):225–227.

40.

Porcu

Sogliano

Ibba

. Failure of gamma-hydroxybutyric acid both to increase neuroactive steroid concentrations in adrenalectomized-orchiectomized rats and to induce tolerance to its steroidogenic effect in intact animals. Brain Res. 2004;1012(1-2):160–168.

41.

Rupprecht

. Neuroactive steroids: mechanisms of action and neuropsychopharmacological properties. Psychoneuroendocrinology. 2003;28(2):139–168.

42.

Paul

Purdy

. Neuroactive steroids. FASEB J. 1992;6(6):2311–2322.

43.

Belelli

Lambert

. Neurosteroids: endogenous regulators of the GABAA receptor. Nat Rev Neurosci. 2005;6(7):565–575.

44.

Bitran

Hilvers

Kellogg

. Anxiolytic effects of 3 alpha-hydroxy-5 alpha[beta]-pregnan-20-one: endogenous metabolites of progesterone that are active at the GABAA receptor. Brain Res. 1991;561(1):157–161.

45.

Wieland

Lan

Mirasedeghi

. Anxiolytic activity of the progesterone metabolite 5α-pregnan-3α-ol-20-one. Brain Res. 1991;565(2):263–268.

46.

Akwa

Purdy

Koob

. The amygdala mediates the anxiolytic-like effect of the neurosteroid allopregnanolone in rat. Behav Brain Res. 1999;106(1):119–125.

47.

Courtney

Polich

. Binge drinking in young adults: data, definitions, and determinants. Psychol Bull. 2009;135(1):142–156.

48.

Jernigan

. Global status report: alcohol and young people. Geneva (CH): World Health Organization; 2001.

49.

Vanderschuren

Pierce

. Sensitization processes in drug addiction. Curr Top Behav Neurosci. 2010;3:179–195.

50.

Hyman

Malenka

Nestler

. Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci. 2006;29:565–598.

51.

Hyman

Malenka

. Addiction and the brain: the neurobiology of compulsion and its persistence. Nat Rev Neurosci. 2001;2(10):695–703.

52.

Koob

Le Moal

. Plasticity of reward neurocircuitry and the ‘dark side’ of drug addiction. Nat Neurosci. 2005;8(11):1442–1444.

53.

Lovallo

. Cortisol secretion patterns in addiction and addiction risk. Int J Psychophysiol. 2006;59(3):195–202.

54.

Holdstock

King

de Wit

. Subjective and objective responses to ethanol in moderate/heavy and light social drinkers. Alcohol Clin Exp Res. 2000;24(6):789–794.

55.

Purdy

Moore

Jr Morrow

. Neurosteroids and GABAA receptor function. Adv Biochem Psychopharmacol. 1992;47:87–92.

56.

Porcu

Morrow

. Divergent neuroactive steroid responses to stress and ethanol in rat and mouse strains: relevance for human studies. Psychopharmacology (Berl). 2014;231(17):3257–3272.

57.

Torres

Ruiz

Ortega

. Effects of CRH and ACTH administration on plasma and brain neurosteroid levels. Neurochem Res. 2001;26(5):555–558.

58.

Torres

Ortega

. Alcohol intoxication increases allopregnanolone levels in female adolescent humans. Neuropsychopharmacology. 2003;28(6):1207–1209.

59.

Torres

Ortega

. Alcohol intoxication increases allopregnanolone levels in male adolescent humans. Psychopharmacology. 2004;172(3):352–355.

60.

Milivojevic

Covault

Sinha

. Effects of plasma allopregnanolone levels on drug craving in cocaine-dependent men and women. Drug Alcohol Depend. 2014;140:e150.

61.

Milivojevic

Kranzler

Gelernter

. Variation in genes encoding the neuroactive steroid synthetic enzymes 5α-reductase type 1 and 3α-reductase type 2 is associated with alcohol dependence. Alcohol Clin Exp Res. 2011;35(5):946–952.

62.

Fox

Sinha

. Sex differences in drug-related stress-system changes: implications for treatment in substance-abusing women. Harv Rev Psychiatry. 2009;17(2):103–119.

63.

Girdler

Lindgren

Porcu

. A history of depression in women is associated with an altered GABAergic neuroactive steroid profile. Psychoneuroendocrinology. 2012;37(4):543–553.

64.

Nyberg

Andersson

Zingmark

. The effect of a low dose of alcohol on allopregnanolone serum concentrations across the menstrual cycle in women with severe premenstrual syndrome and controls. Psychoneuroendocrinology. 2005;30(9):892–901.

65.

Reich

Cummings

Greenbaum

. The temporal “pulse” of drinking: tracking 5 years of binge drinking in emerging adults. J Abnorm Psychol. 2015;124(3):635–647.

66.

O Malley

. Maturing out of problematic alcohol use. Alcohol Res Health. 2004;28(4):202–204.

67.

King

de Wit

McNamara

. Rewarding, stimulant, and sedative alcohol responses and relationship to future binge drinking. Arch Gen Psychiatry. 2011;68(4):389–399.

68.

King

Hasin

O’Connor

. A prospective 5-year re-examination of alcohol response in heavy drinkers progressing in alcohol use disorder (AUD). Biol Psychiatry. 2015 5 14; Epub ahead of print.

69.

King

McNamara

Hasin

. Alcohol challenge responses predict future alcohol use disorder symptoms: a 6-year prospective study. Biol Psychiatry. 2014;75(10):798–806.

70.

McEwen

. Stress, adaptation, and disease: allostasis and allostatic load. Ann N Y Acad Sci. 1998;840(1):33–44.

71.

Sinha

. Modeling relapse situations in the human laboratory. Curr Top Behav Neurosci. 2013;13:379–402.

72.

Sinha

Fox

Hong

. Enhanced negative emotion and alcohol craving, and altered physiological responses following stress and cue exposure in alcohol dependent individuals. Neuropsychopharmacology. 2009;34(5):1198–1208.

73.

Sinha

Fox

Hong

. Effects of adrenal sensitivity, stress- and cue-induced craving, and anxiety on subsequent alcohol relapse and treatment outcomes. Arch Gen Psychiatry. 2011;68(9):942–952.

74.

Junghanns

Tietz

Dibbelt

. Attenuated salivary cortisol secretion under cue exposure is associated with early relapse. Alcohol Alcohol. 2005;40(1):80–85.

75.

Volkow

Wang

Telang

. Profound decreases in dopamine release in striatum in detoxified alcoholics: possible orbitofrontal involvement. J Neurosci. 2007;27(46):12700–12706.

76.

Volkow

Wang

G-J

Maynard

. Effects of alcohol detoxification on dopamine D2 receptors in alcoholics: a preliminary study. Psychiatry Res. 2002;116(3):163–172.

77.

Guardia

Catafau

Batlle

. Striatal dopaminergic D(2) receptor density measured by [(123)I]iodobenzamide SPECT in the prediction of treatment outcome of alcohol-dependent patients. Am J Psychiatry. 2000;157(1):127–129.

78.

Heilig

Egli

Crabbe

. Acute withdrawal, protracted abstinence and negative affect in alcoholism: are they linked? Addict Biol. 2010;15(2):169–184.

79.

Matikainen

Juntunen

Salmi

. Autonomic dysfunction in long-standing alcoholism. Alcohol Alcohol. 1986;21(1):69–73.

80.

Buijs

Van Eden

. The integration of stress by the hypothalamus, amygdala and prefrontal cortex: balance between the autonomic nervous system and the neuroendocrine system. Prog Brain Res. 2000;126:117–132

81.

Hawley

Major

Schulman

. Cerebrospinal fluid 3-methoxy-4-hydroxyphenylglycol and norepinephrine levels in alcohol withdrawal: correlations with clinical signs. Arch Gen Psychiatry. 1985;42(11):1056–1062.

82.

Hawley

Nemeroff

Bissette

. Neurochemical correlates of sympathetic activation during severe alcohol withdrawal. Alcohol Clin Exp Res. 1994;18(6):1312–1316.

83.

Birnbaum

Gobeske

Auerbach

. A role for norepinephrine in stress-induced cognitive deficits: α-1-adrenoceptor mediation in the prefrontal cortex. Biol Psychiatry. 1999;46(9):1266–1274.

84.

Volkow

Wang

Fowler

. Addiction: decreased reward sensitivity and increased expectation sensitivity conspire to overwhelm the brain’s control circuit. Bioessays. 2010;32(9):748–755.

85.

Quintana

McGregor

Guastella

. A meta-analysis on the impact of alcohol dependence on short-term resting-state heart rate variability: implications for cardiovascular risk. Alcohol Clin Exp Res. 2013;37(Suppl 1):E23–E29.

86.

Stormark

Laberg

Nordby

. Heart rate responses indicate locked-in attention in alcoholics immediately prior to drinking. Addict Behav. 1998;23(2):251–255.

87.

Thayer

Hall

Sollers

. Alcohol use, urinary cortisol, and heart rate variability in apparently healthy men: evidence for impaired inhibitory control of the HPA axis in heavy drinkers. Int J Psychophysiol. 2006;59(3):244–250.

88.

Morrow

VanDoren

Penland

. The role of GABAergic neuroactive steroids in ethanol action, tolerance and dependence. Brain Res Brain Res Rev. 2001;37(1):98–109.

89.

Romeo

Brancati

De Lorenzo

. Marked decrease of plasma neuroactive steroids during alcohol withdrawal. Clin Neuropharmacol. 1996;19(4):366–369.

90.

Gordon

Altman

Southren

. Effect of alcohol (ethanol) administration on sex-hormone metabolism in normal men. New Engl J Med. 1976;295(15):793–797.

91.

Alyea

Watson

. Nongenomic mechanisms of physiological estrogen-mediated dopamine efflux. BMC Neurosci. 2009;10:59.

92.

Ogilvie

Rivier

. Gender difference in hypothalamic–pituitary–adrenal axis response to alcohol in the rat: activational role of gonadal steroids. Brain Res. 1997;766(1):19–28.

93.

Jones

. Alcohol effects in women during the menstrual cycle. Ann N Y Acad Sci. 1976;273:576–587.

94.

Pohorecky

. Stress and alcohol interaction: an update of human research. Alcohol Clin Exp Res. 1991;15(3):438–459.

95.

Chaplin

Hong

Bergquist

. Gender differences in response to emotional stress: an assessment across subjective, behavioral, and physiological domains and relations to alcohol craving. Alcohol Clin Exp Res. 2008;32(7):1242–1250.

96.

Adinoff

Junghanns

Kiefer

. Suppression of the HPA axis stress-response: implications for relapse. Alcohol Clin Exp Res. 2005;29(7):1351–1355.

97.

Breese

Sinha

Heilig

. Chronic alcohol neuroadaptation and stress contribute to susceptibility for alcohol craving and relapse. Pharmacol Ther. 2011;129(2):149–171.

98.

Shansky

Lipps

. Stress-induced cognitive dysfunction: hormone-neurotransmitter interactions in the prefrontal cortex. Front Hum Neurosci. 2013;7:123.

99.

Barker

Corbit

Robinson

. Corticostriatal circuitry and habitual ethanol seeking. Alcohol. 2015;49(8):817–824.

100.

Miller

Cohen

. An integrative theory of prefrontal cortex function. Annu Rev Neurosci. 2001;24(1):167–202.

101.

Abernathy

Chandler

Woodward

. Alcohol and the prefrontal cortex. Int Rev Neurobiol. 2010;91:289–320.

102.

Thayer

Åhs

Fredrikson

. A meta-analysis of heart rate variability and neuroimaging studies: implications for heart rate variability as a marker of stress and health. Neurosci Biobehav Rev. 2012;36(2):747–756.

103.

Radley

Arias

Sawchenko

. Regional differentiation of the medial prefrontal cortex in regulating adaptive responses to acute emotional stress. J Neurosci. 2006;26(50):12967–12976.

104.

Spencer

Buller

Day

. Medial prefrontal cortex control of the paraventricular hypothalamic nucleus response to psychological stress: possible role of the bed nucleus of the stria terminalis. J Comp Neurol. 2005;481(4):363–376.

105.

Radley

Gosselink

Sawchenko

. A discrete GABAergic relay mediates medial prefrontal cortical inhibition of the neuroendocrine stress response. J Neurosci. 2009;29(22):7330–7340.

106.

Richardson

. Alcohol, stress hormones, and the prefrontal cortex: a proposed pathway to the dark side of addiction. Neuroscience. 2014;277:139–151.

107.

Gamo

Arnsten

. Molecular modulation of prefrontal cortex: rational development of treatments for psychiatric disorders. Behav Neurosci. 2011;125(3):282–296.

108.

Rosenkranz

Grace

. Cellular mechanisms of infralimbic and prelimbic prefrontal cortical inhibition and dopaminergic modulation of basolateral amygdala neurons in vivo. J Neurosci. 2002;22(1):324–337.

109.

McEwen

Morrison

. The brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course. Neuron. 2013;79(1):16–29.

110.

Bechara

. Decision making, impulse control and loss of willpower to resist drugs: a neurocognitive perspective. Nat Neurosci. 2005;8(11):1458–1463.

111.

Seo

Lacadie

Tuit

. Disrupted ventromedial prefrontal function, alcohol craving, and subsequent relapse risk. JAMA Psychiatry. 2013;70(7):727–739.

112.

Heinz

Beck

Grüsser

. Identifying the neural circuitry of alcohol craving and relapse vulnerability. Addict Biol. 2009;14(1):108–118.

113.

Seo

Sinha

. The neurobiology of alcohol craving and relapse. Handb Clin Neurol. 2014;125:355–368.

114.

Lee

Park

Kim

. Effects of naltrexone on the ethanol-induced changes in the rat central dopaminergic system. Alcohol Alcohol. 2005;40(4):297–301.

115.

O’Malley

Krishnan-Sarin

Farren

. Naltrexone decreases craving and alcohol self-administration in alcohol-dependent subjects and activates the hypothalamo–pituitary–adrenocortical axis. Psychopharmacology. 2002;160(1):19–29.

116.

McCaul

Wand

Stauffer

. Naltrexone dampens ethanol-induced cardiovascular and hypothalamic-pituitary-adrenal axis activation. Neuropsychopharmacology. 2001;25(4):537–547.

Alcohol Effects on Stress Pathways

Abstract

Keywords

Acute Alcohol Intake Activates Stress Regulation Systems

Binge Alcohol Consumption Sensitizes Reward Pathways by Altering Stress Regulation System Function

Chronic, Heavy Alcohol Consumption Is Associated With Neuroendocrine Tolerance in Stress Regulation Systems

Allostatic Overload Decreases Prefrontal Regulation of Stress Pathways

Future Research to Target Hypothalamic and Extrahypothalamic Stress Regulation Systems in Treatment of AUDs

Footnotes

Declaration of Conflicting Interests

Funding

References