Alcohol, stress, and glucocorticoids: From risk to dependence and relapse in alcohol use disorders

“This return to a healthy normal set-point occurs via allostatic processes, which allow the brain and body to achieve physiological stability through challenges to homeostasis by altering cellular structure and function (McEwen, 1998).”

“…relays leads to damage via glucocorticoid -induced excitotoxicity, then self-directed behavior may be even more likely to be replaced by habit and sensory-driven automatic responding (Bechara, 2005; Ochsner and Gross, 2005; Ochsner et al., 2004; Rosenkranz and Grace, 2002; Thayer et al., 2009).”

“Under normal conditions, the PFC can inhibit the physiological response to stress that is related to activation of the HPA axis and the autonomic nervous system (Spencer et al., 2005; Ulrich-Lai and Herman, 2009).”

“…AUDs, i.e., decreases in working memory function, poor attention and flexibility, lower behavioral control, and increases in impulsive responding (Arnsten, 2009a; Bechara, 2005; Koob and Le Moal, 2005; Matikainen et al., 1986; Piazza and Le Moal, 1997; Rosenkranz and Grace, 2002; Volkow et al.,…”

“…. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145 Eighteen percent of Americans suffer from an alcohol use disorder (AUD) at some point during their lifetime and up to 8% of Americans go on to develop severe AUDs (Hasin et al., 2007).”

“…consumption results in larger-scale adaptations and wear and tear (allostatic overload) to the reward and neuroendocrine regulation circuits (Koob and Le Moal, 2005; Sinha, 2001); these adaptations may represent the pathophysiology underlying the transition from controlled to compulsive…”

“A wealth of preclinical and clinical data indicates that acute stressors may play a role in the motivation for alcohol consumption in those with and without AUDs (Chaplin et al., 2008; Goeders, 2004; Sinha, 2001; Uhart and Wand, 2009).”

“…relays leads to damage via glucocorticoid -induced excitotoxicity, then self-directed behavior may be even more likely to be replaced by habit and sensory-driven automatic responding (Bechara, 2005; Ochsner and Gross, 2005; Ochsner et al., 2004; Rosenkranz and Grace, 2002; Thayer et al., 2009).”

“…relays leads to damage via glucocorticoid -induced excitotoxicity, then self-directed behavior may be even more likely to be replaced by habit and sensory-driven automatic responding (Bechara, 2005; Ochsner and Gross, 2005; Ochsner et al., 2004; Rosenkranz and Grace, 2002; Thayer et al., 2009).”

“…responses that are associated with decreased prefrontal executive control over stress and reward systems, which may result in increased craving and a greater susceptibility to habit-based maladaptive coping, i.e., relapse to drinking behavior (Heinz et al., 2009; Seo and Sinha, 2014; Sinha, 2008a).”

“…relays leads to damage via glucocorticoid -induced excitotoxicity, then self-directed behavior may be even more likely to be replaced by habit and sensory-driven automatic responding (Bechara, 2005; Ochsner and Gross, 2005; Ochsner et al., 2004; Rosenkranz and Grace, 2002; Thayer et al., 2009).”

“CRF in the amygdala and PFC has been linked to autonomic arousal and stress enhancement of PFC dependent memory via its effects on dopamine and norepinephrine (Herman et al., 2003, 2005; Roozendaal et al., 2002).”

“…in larger-scale adaptations and wear and tear (allostatic overload) to the reward and neuroendocrine regulation circuits (Koob and Le Moal, 2005; Sinha, 2001); these adaptations may represent the pathophysiology underlying the transition from controlled to compulsive alcohol-seeking in humans…”

“CRF in the amygdala and PFC has been linked to autonomic arousal and stress enhancement of PFC dependent memory via its effects on dopamine and norepinephrine (Herman et al., 2003, 2005; Roozendaal et al., 2002).”

“Additionally, the amount of alcohol consumed within a drinking episode is enhanced via explicit expectancies regarding alcohol-induced increases in stimulation and these expectancies develop based on past experiences with alcohol (Kreusch et al., 2013).”

“This positive valence is further encoded by neuroplasticity in the afferent connections of the NAcc to PFC; over repeated use, these connections become overly sensitive to alcohol and increase the motivational drive to consume alcohol (Liu et al., 2011).”

“…i.e., decreases in working memory function, poor attention and flexibility, lower behavioral control, and increases in impulsive responding (Arnsten, 2009a; Bechara, 2005; Koob and Le Moal, 2005; Matikainen et al., 1986; Piazza and Le Moal, 1997; Rosenkranz and Grace, 2002; Volkow et al., 2010).”

“…individuals 50 mg/day of naltrexone or placebo for 6 days in a double blind manner and assessed their responses to an initial alcohol priming drink of 0.03 g/dl followed by a selfadministration period with an opportunity to drink up to 8 drinks in a two-hour period (O'Malley et al., 2002).”

“Current models of the development of severe AUDs posit that a shift occurs from alcohol consumption in impulsive binge intoxication episodes to compulsive use accompanied by cognitive preoccupationwith alcohol (Koob and Le Moal, 1997).”

“appraising emotion and stress states and also exercising selfcontrol over emotions, desires, and impulses (Maier and Watkins, 2010; Roberts et al., 1998).”

“…continued high basal ACTH and cortisol as well as higher basal heart rates, and blunted or suppressed ACTH, cortisol, and heart rate responses to pharmacological and psychological challenges in alcohol dependent individuals (Fox et al., 2008, 2012a; Sinha, 2012; Sinha et al., 2012, 2011a, 2009b).”

“Specifically, acute withdrawal states are associated with increases in CRF levels in cerebrospinal fluid and blood plasma levels of ACTH, cortisol, norepinephrine, and epinephrine (Breese et al., 2011; D’Sa et al., 2012; Hawley et al., 1985; Heilig et al., 2010; Markus et al., 2002).”

“…models of addiction, such as the tension-reduction and self-medication models, which emphasize the basic need to boost positive affect via either positive (mood enhancement) or negative (relief from stress) reinforcement processes (Swendsen et al., 2000; Verheul et al., 1999; Weiss et al., 1992).”

“In support of this, it was demonstrated that hypersensitive amygdala activity blocks PFC inhibition in order to maximize external sensory input and respond to potential danger in the environment (Rosenkranz and Grace, 2002).”

“…in non-dependent drinkers generally support the notion that acute exposure to stress or high ratings of negative mood and stress are associated with alcohol use for coping (Breese et al., 2005; Cooney et al., 1997; Dvorak et al., 2014; Litt and Cooney, 1999; Serre et al., 2015; Todd et al., 2009).”

“We also showed that both the persistent enhanced basal stress state and also the blunted responses to stress, alongwith high stress-induced alcohol craving, modulated the propensity for these early abstinent, treatment engaged AUD individuals to future alcohol relapse (Sinha et al., 2011b).”

“However, as individuals progress into AUDs, alcohol consumption is driven more by negative reinforcement and less by the euphoric effects in all users, with alcohol providing relief from uncomfortable and unpredictable affective states (Koob, 2013).”

“…models of addiction, such as the tension-reduction and self-medication models, which emphasize the basic need to boost positive affect via either positive (mood enhancement) or negative (relief from stress) reinforcement processes (Swendsen et al., 2000; Verheul et al., 1999; Weiss et al., 1992).”

“For example, positron emission tomography (PET) studies have shown that stress-induced cortisol levels positively correlate with amphetamine-induced dopamine release in the ventral striatum and amphetamine-induced “high” (Oswald et al., 2005; Wand et al., 2007).”

“Human laboratory models can be effectively used to assess whether treatment with specific pharmacological compounds, versus placebo, can address alcohol-related disruptions in HPA axis function, as well as alcohol craving and intake (Sinha, 2009; Sinha et al., 2009a, 2011b).”

“For example, acute uncontrollable stress-such as with acute trauma-also up-regulates serine protease tissue-plasminogen activator in the amygdala, resulting in stress-related anxious behavior in mice (Pawlak et al., 2003) and elicits heightened amygdala response and subsequent indiscriminate hypervigilance in humans (…”

“…of a return to drinking on a sensitized stress system have been broadly highlighted by the fact that treatment and laboratory studies have documented stress and negative mood as robust predictors of both medication response (Sofuoglu et al., 2013) and treatment outcome (Mulvaney et al., 1999).”

“appraising emotion and stress states and also exercising selfcontrol over emotions, desires, and impulses (Maier and Watkins, 2010; Roberts et al., 1998).”

“Chronic a1 receptor stimulation in the PFC is known to impair attentional processes by attenuating salient “signals” and increasing irrelevant “noise” (Birnbaum et al., 1999).”

“Naltrexone (NTX) is an approved medication for AUDs and has been shown to have a modest, but significant effect as an anticraving medication for AUDs (O'Brien et al., 1996; O'Malley et al., 1996; O'Malley et al., 1992; Volpicelli et al., 1992).”

“Also, the inability to resist nicotine under stress is linked to cortisol release and the “high” feeling associated with return to cigarette smoking after stress exposure (McKee et al., 2011).”

“Specifically, with binge and heavy alcohol use, a neuroendocrine tolerance response to stress and alcohol intake is observed (Allen et al., 2011; Heilig et al., 2010; Lovallo, 2006).”

“Specifically, the PFC inhibits PVN activity via the GABAergic interneurons of the bed nucleus stria termanalis (Radley et al., 2009).”

“…consumption, from the associated psychological and interpersonal stress, which can then be worsened by maladaptive “drinking to cope” binges (Fox et al., 2005, 2007; Holahan et al., 2001; Park and Levenson, 2002; Sinha et al., 2009a; Thomas et al., 2003) (see Breese et al., 2011 for review).”

“ened by maladaptive “drinking to cope” binges (Fox et al., 2005, 2007; Holahan et al., 2001; Park and Levenson, 2002; Sinha et al., 2009a; Thomas et al., 2003) (see Breese et al.”

“Through repeated cycles of binge consumption and withdrawal, there are significant increases in neuroendocrine tolerance and basal state autonomic upregulation (Breese et al., 2011; Sinha et al., 2011a,b).”

“…wear and tear (allostatic overload) to the reward and neuroendocrine regulation circuits (Koob and Le Moal, 2005; Sinha, 2001); these adaptations may represent the pathophysiology underlying the transition from controlled to compulsive alcohol-seeking in humans (Sinha, 2013; Sinha et al., 2013).”

“CRF in the amygdala and PFC has been linked to autonomic arousal and stress enhancement of PFC dependent memory via its effects on dopamine and norepinephrine (Herman et al., 2003, 2005; Roozendaal et al., 2002).”

“…in non-dependent drinkers generally support the notion that acute exposure to stress or high ratings of negative mood and stress are associated with alcohol use for coping (Breese et al., 2005; Cooney et al., 1997; Dvorak et al., 2014; Litt and Cooney, 1999; Serre et al., 2015; Todd et al., 2009).”

“2 (Blaine et al., 2016; Sinha et al., 2016).”

“A wealth of preclinical and clinical data indicates that acute stressors may play a role in the motivation for alcohol consumption in those with and without AUDs (Chaplin et al., 2008; Goeders, 2004; Sinha, 2001; Uhart and Wand, 2009).”

“For example, acute intoxication at or above 0.08 g% is associated with hypothalamically-driven rises in blood cortisol, ACTH, and norepinephrine (Allen et al., 2011; Borg et al., 1981; Frias et al., 2000; Gianoulakis et al., 1996; Howes and Reid, 1985; Magrys et al., 2013).”

“…models of addiction, such as the tension-reduction and self-medication models, which emphasize the basic need to boost positive affect via either positive (mood enhancement) or negative (relief from stress) reinforcement processes (Swendsen et al., 2000; Verheul et al., 1999; Weiss et al., 1992).”

“Therefore, binge and heavy alcohol-associated adaptations in HPA axis and glucocorticoids may not only represent an opponent process that promotes neuroendocrine tolerance, but also result in adaptations that increase compulsivemotivation to restore reward tone or hedonic homeostasis (Koob, 1996).”

“The greater stimulating effects of alcohol consumption in FHP versus FHN subjects may be related to data showing that FHP adolescent boys have blunted basal (tonic) cortisol levels (Schuckit, 1987; Schuckit et al., 1996) and that blunted cortisol in boys promote alcohol and drug intake in adolescence (Moss et al.”

“A number of studies have demonstrated that binge/heavy drinkers show a blunted cortisol response to a fixed moderate or high dose oral alcohol administration and to pharmacological challenges, compared to moderate social drinkers (Allen et al., 2011; Frias et al., 2000; Mick et al., 2013; S€ oderpalm Gordh and S€ oder…”

“Recent evidence from human studies suggests that acute stress-related increases in glucocorticoids and catecholamines are both required for encoding rewarding or aversive value and reinforcement learning, such as learning related to alcohol consumption as a stress-coping mechanism (Belujon and Grace, 2015; Schwabe et…”

“Naltrexone (NTX) is an approved medication for AUDs and has been shown to have a modest, but significant effect as an anticraving medication for AUDs (O'Brien et al., 1996; O'Malley et al., 1996; O'Malley et al., 1992; Volpicelli et al., 1992).”

“Recent evidence from human studies suggests that acute stress-related increases in glucocorticoids and catecholamines are both required for encoding rewarding or aversive value and reinforcement learning, such as learning related to alcohol consumption as a stress-coping mechanism (Belujon and Grace, 2015; Schwabe et…”

“Additionally, alcohol's initial stimulating effects include increased autonomic and HPA axis arousal and these effects may further potentiate both stress and alcohol-related striatal transmission to influence motivation and reward value of alcohol (Lee and Rivier, 1997).”

“ened by maladaptive “drinking to cope” binges (Fox et al., 2005, 2007; Holahan et al., 2001; Park and Levenson, 2002; Sinha et al., 2009a; Thomas et al., 2003) (see Breese et al.”

“…reported by binge drinkers matches predictions based on a state of mesocortical sensitization and neuroendocrine tolerance: binge drinkers report that one drink increases craving and stimulation, while light social drinkers report that one drink is anxiolytic and sedating (Holdstock et al., 2000).”

“Under normal conditions, the PFC can inhibit the physiological response to stress that is related to activation of the HPA axis and the autonomic nervous system (Spencer et al., 2005; Ulrich-Lai and Herman, 2009).”

“However, there were dose related effects, with the 3 mg/day effect showing better outcomes and greater efficacy in cocaine and alcohol abusing women than men (Fox et al., 2015); some gender effects have also been noted in tobacco cessation effects (Glassman et al., 1993).”

“nucleus accumbens (NAcc) signal its positively reinforcing effects (Spanagel et al., 2014; Yorgason et al., 2014).”

“Importantly, CRF also has extensive influence in extrahypothalamic regions and across the corticostriatal-limbic pathways, as it modulates the levels of central catecholamines, particularly norepinephrine and dopamine in the Prefrontal Cortex (PFC; (Lavicky and Dunn, 1993).”

“previously reported in a pilot study that Prazosin reduced alcohol intake (Simpson et al., 2009), and Prazosin and the related com-”

“…control functioning occur with multiple detoxifications and each successive detoxification is also known to jeopardize abstinence and alcohol recovery, in addition to performance in emotion and incentive conflict tasks in alcohol dependent individuals (Duka et al., 2011; O'Daly et al., 2012).”

“…in non-dependent drinkers generally support the notion that acute exposure to stress or high ratings of negative mood and stress are associated with alcohol use for coping (Breese et al., 2005; Cooney et al., 1997; Dvorak et al., 2014; Litt and Cooney, 1999; Serre et al., 2015; Todd et al., 2009).”

“…through their late twenties and early thirties 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 (King et al., 2015, 2011, 2014).”

“The greater stimulating effects of alcohol consumption in FHP versus FHN subjects may be related to data showing that FHP adolescent boys have blunted basal (tonic) cortisol levels (Schuckit, 1987; Schuckit et al., 1996) and that blunted cortisol in boys promote alcohol and drug intake in adolescence (Moss et al.”

“Progesterone has been shown to decrease the subjective effects of cocaine (Sofuoglu et al., 2004) and improve cocaine use outcomes (Yonkers et al., 2014) and we previously showed that progesterone (400 mg/day) versus placebo administered for 7 days reduced cue-induced cocaine craving and improved…”

“Furthermore, chronic basal cortisol and norepinephrine exposure from chronic alcohol or stress can maintain excitotoxic cascades that result in decreased dendritic length and decreased spine density of the dendrites in the PFC (Gamo and Arnsten, 2011; Karatsoreos and McEwen, 2013).”

“in binge/heavy versus moderate drinking groups (Bjork and Gilman, 2014; Sripada et al., 2011).”

“Specifically, acute withdrawal states are associated with increases in CRF levels in cerebrospinal fluid and blood plasma levels of ACTH, cortisol, norepinephrine, and epinephrine (Breese et al., 2011; D’Sa et al., 2012; Hawley et al., 1985; Heilig et al., 2010; Markus et al., 2002).”

“08 g% is associated with hypothalamically-driven rises in blood cortisol, ACTH, and norepinephrine (Allen et al., 2011; Borg et al., 1981; Frias et al., 2000; Gianoulakis et al., 1996; Howes and Reid, 1985; Magrys et al., 2013).”

“…effects of alcohol consumption in FHP versus FHN subjects may be related to data showing that FHP adolescent boys have blunted basal (tonic) cortisol levels (Schuckit, 1987; Schuckit et al., 1996) and that blunted cortisol in boys promote alcohol and drug intake in adolescence (Moss et al., 1999).”

“in binge/heavy versus moderate drinking groups (Bjork and Gilman, 2014; Sripada et al., 2011).”

“The allostatic overload in these systems may also weaken the regulatory influence of the PFC over hypothalamic and extrahypothalamic stress and reward circuits (Seo and Sinha, 2014; Sullivan and Pfefferbaum, 2014), and prevent restored functioning of these pathways to support alcoholism recovery.”

“A number of studies have demonstrated that binge/heavy drinkers show a blunted cortisol response to a fixed moderate or high dose oral alcohol administration and to pharmacological challenges, compared to moderate social drinkers (Allen et al., 2011; Frias et al., 2000; Mick et al., 2013; S€ oderpalm Gordh and S€ oder…”

“…of a return to drinking on a sensitized stress system have been broadly highlighted by the fact that treatment and laboratory studies have documented stress and negative mood as robust predictors of both medication response (Sofuoglu et al., 2013) and treatment outcome (Mulvaney et al., 1999).”

“…in non-dependent drinkers generally support the notion that acute exposure to stress or high ratings of negative mood and stress are associated with alcohol use for coping (Breese et al., 2005; Cooney et al., 1997; Dvorak et al., 2014; Litt and Cooney, 1999; Serre et al., 2015; Todd et al., 2009).”

“Indeed, we found that the high ALLO group (treated with progesterone) versus the low ALLO group showed reduced overall drug and alcohol craving, improved Stroop performance, and both reductions in basal cortisol levels as well as increased cortisol in response to stress (Milivojevic et al., 2016).”

“For example, acute intoxication at or above 0.08 g% is associated with hypothalamically-driven rises in blood cortisol, ACTH, and norepinephrine (Allen et al., 2011; Borg et al., 1981; Frias et al., 2000; Gianoulakis et al., 1996; Howes and Reid, 1985; Magrys et al., 2013).”

“This blunted stimulant response is also related to greater acute tolerance to alcohol and thus may contribute to greater consumption (Ramchandani et al., 2002).”

“…in non-dependent drinkers generally support the notion that acute exposure to stress or high ratings of negative mood and stress are associated with alcohol use for coping (Breese et al., 2005; Cooney et al., 1997; Dvorak et al., 2014; Litt and Cooney, 1999; Serre et al., 2015; Todd et al., 2009).”

“Progesterone has been shown to decrease the subjective effects of cocaine (Sofuoglu et al., 2004) and improve cocaine use outcomes (Yonkers et al., 2014) and we previously showed that progesterone (400 mg/day) versus placebo administered for 7 days reduced cue-induced cocaine craving and improved…”

“For example, acute intoxication at or above 0.08 g% is associated with hypothalamically-driven rises in blood cortisol, ACTH, and norepinephrine (Allen et al., 2011; Borg et al., 1981; Frias et al., 2000; Gianoulakis et al., 1996; Howes and Reid, 1985; Magrys et al., 2013).”

“…AUDs, i.e., decreases in working memory function, poor attention and flexibility, lower behavioral control, and increases in impulsive responding (Arnsten, 2009a; Bechara, 2005; Koob and Le Moal, 2005; Matikainen et al., 1986; Piazza and Le Moal, 1997; Rosenkranz and Grace, 2002; Volkow et al.,…”

“…cortisol response to a fixed moderate or high dose oral alcohol administration and to pharmacological challenges, compared to moderate social drinkers (Allen et al., 2011; Frias et al., 2000; Mick et al., 2013; S€oderpalm Gordh and S€oderpalm, 2011; Thayer et al., 2006; Waltman et al., 1993).”

“…i.e., decreases in working memory function, poor attention and flexibility, lower behavioral control, and increases in impulsive responding (Arnsten, 2009a; Bechara, 2005; Koob and Le Moal, 2005; Matikainen et al., 1986; Piazza and Le Moal, 1997; Rosenkranz and Grace, 2002; Volkow et al., 2010).”

“nucleus accumbens (NAcc) signal its positively reinforcing effects (Spanagel et al., 2014; Yorgason et al., 2014).”

“08 g% is associated with hypothalamically-driven rises in blood cortisol, ACTH, and norepinephrine (Allen et al., 2011; Borg et al., 1981; Frias et al., 2000; Gianoulakis et al., 1996; Howes and Reid, 1985; Magrys et al., 2013).”

“A number of studies have demonstrated that binge/heavy drinkers show a blunted cortisol response to a fixed moderate or high dose oral alcohol administration and to pharmacological challenges, compared to moderate social drinkers (Allen et al., 2011; Frias et al., 2000; Mick et al., 2013; S€ oderpalm Gordh and S€ oder…”

“…i.e., decreases in working memory function, poor attention and flexibility, lower behavioral control, and increases in impulsive responding (Arnsten, 2009a; Bechara, 2005; Koob and Le Moal, 2005; Matikainen et al., 1986; Piazza and Le Moal, 1997; Rosenkranz and Grace, 2002; Volkow et al., 2010).”

“…effects of alcohol consumption in FHP versus FHN subjects may be related to data showing that FHP adolescent boys have blunted basal (tonic) cortisol levels (Schuckit, 1987; Schuckit et al., 1996) and that blunted cortisol in boys promote alcohol and drug intake in adolescence (Moss et al., 1999).”

“It is well-documented that stress, both acute and chronic, is a trigger for alcohol (mis) use (Becker, Lopez, & Doremus-Fitzwater, 2011; Blaine & Sinha, 2017).”

“…disruption can change the basal subjective state and physiologic tone, the phasic stress response, as well as the stress recovery phase without a return to homeostasis, as discussed in previous psychosocial and psychobiological stress adaptation models (43, 44) and illustrated in Figure 1, C and D.”

“In humans, enhanced stress-system activity has been associated with chronic smoking as well as with cocaine and alcohol consumption [38, 39].”

“Furthermore, these results indicate that the ventromedial PFC, including OFC, may be a key component of the influence of stress on problematic alcohol use (Blaine and Sinha, 2017).”

“Both acute and chronic stress are documented risk factors of increased alcohol use [8,9].”

“Importantly, women with AUD experience greater craving to drink following exposure to stressful images (Hartwell and Ray, 2013) and stronger relationships between past trauma severity and craving (Heffner et al., 2011), relative to men.”

“Stress and the release of stress hormones by the hypothalamic–pituitary–adrenal (HPA) axis have been implicated in binge/heavy drinking, motivation to drink, and the chronic relapsing nature of AUD (Blaine and Sinha, 2017; Stephens and Wand, 2012).”

“These results are consistent with current understanding of the underlying neurobiology of AUD, that chronic alcohol-related neuroadaptations in prefrontal-ventral striatal circuits may hamper a person’s ability to recruit prefrontal executive control functions in response to stress cues, while also showing hypoactivat…”

“For example, relative to controls, MS increases dopamine, endogenous opioid, and CRH expression simultaneously in NAc in male mice that also show increased ethanol consumption relative to controls (García- Gutiérrez et al., 2016).”

“The latter effect is in line with a well-documented clinical relationship between HPA axis activity, craving, and relapse to alcohol use (Blaine & Sinha, 2017; Sinha et al., 2011; Stephens & Wand, 2012).”

“Stress, depression and anxiety are conditions associated with alcohol consumption and smoking during the SARSCoV-2 outbreak [7, 13, 15, 16], as they act as triggers for consumption as a way of coping [7, 17, 18].”

“King and colleagues (King et al, 2006; King et al, 2014) demonstrated in a series of longitudinal studies that problem drinkers who experience high stimulation in response to alcohol consumption go on to develop AUDs, whereas those drinkers who experienced sedative effects of alcohol Alcohol.”

“diovascular system in the same way flexibility is thought to be lost in other body systems such as the hypothalamic–pituitary adrenal axis under repeated intoxication–withdrawal.(31) Thus, less accurate infor-”

“Chronic activation of the HPA axis causes sustained cortisol to increase and altered stress responses, which is a common occurrence in substance addiction [35].”

“Alternatively, deficits in 2-AG could be altering the ability of the vmPFC to exert efficient glucocorticoid-mediated negative feedback inhibition over the HPA axis, which has recently been suggested as a potential biomarker of alcohol dependence risk and relapse (Blaine and Sinha, 2017).”

“Binge and hazardous alcohol drinking patterns are associated with well-documented changes both in the brain stress and emotion regions, such as the amygdala,(8,12) and in associated brain networks, including the ventral and dorsal striatum as well as the OFC, VmPFC, and dorsolateral prefrontal cortex.(9,12,14,15)”

“, reinstatement drug seeking, withdrawal) [149].”

“There is a rich literature documenting alterations in HPA reactivity after alcohol exposure and dependence (Stephens and Wand, 2012, Blaine and Sinha, 2017), but dysregulated HPA responses may also precede and be predictive of high alcohol intake.”

“Withdrawal is thought to promote negative reinforcement drinking via alterations of the HPA axis (Blaine and Sinha 2017; Koob 2003; Rasmussen et al.”

“Ethanol activates neuroendocrine stress systems, which become dysregulated following chronic exposure contributing to AUD [9, 10].”

“…treatment of alcoholism (Davies et al., 2012), particularly to specifically target stress-system psychopathology during early and protracted abstinence, known to underlie high craving, anxiety and excessive drinking and relapse risk (Blaine and Sinha, 2017, Milivojevic and Sinha, 2018, Koob, 2008).”

“2007), which may contribute to the maintenance of alcohol use as an anxiolytic (Blaine and Sinha 2017).”

“Alcohol also has activating effects and interacts with glucocorticoid receptors (Blaine and Sinha, 2017).”

“Repeated exposure to alcohol withdrawal and concomitant AW results in disruption of the PFC-striatal pathway that in turn facilitates stress-related and alcohol cue-related excessive drinking to influence AUD course and risk of treatment failure.(12,40) Significant heterogeneity in AUD clinical features has resulted i…”

“While acute low to moderate alcohol in social drinkers stimulates autonomic and neuroendocrine arousal (see (Blaine and Sinha 2017) for review), chronic alcohol use results in significant adaptations in stress arousal with increased basal autonomic tone and blunted autonomic and HPA axis responsivity (Adinoff et al.”

“Interrupting mGlu5 phosphorylation reduces anxiety and increases novelty-seeking Alcohol is an anxiolytic and this property can contribute to its abuse liability, particularly in hyper-anxious individuals (Becker, 2017; Blaine and Sinha, 2017).”

“These effects potentiate both stress and alcohol-related effects on motivation and reinforcement learning [40] which can further facilitate alcohol use as a stress-related coping mechanism [38].”

“Chronic heavy alcohol use and alcohol withdrawal can also alter the regulation of the HPA axis.(16,17) Alcohol directly stimulates the secretion of CRH within the paraventricular nuclei of the hypothalami with high doses of alcohol leading to elevated circulating adrenocorticotropic hormone (ACTH) and cortisol levels.”

“, 2010), while stress is a primary trigger for alcohol craving and relapse in alcoholic patients (Blaine and Sinha, 2017).”

“Given that stress is known to significantly influence ethanol consumption (Becker, 2017; Becker et al., 2011; Blaine and Sinha, 2017; Sinha, 2012; Spanagel et al., 2014) and that both stress and ethanol exposure alter BDNF activity in brain, it is surprising that very little is known about their combined effects on BD…”

“…cortisol levels in both dependent animals and humans and alcohol withdrawal is associated with increased cortisol levels, which remain elevated even during sustained abstinence compared to healthy subjects, suggesting persistent HPA neuroadaptations (Blaine and Sinha, 2017; Wemm and Sinha, 2019).”

“…arthritis; Affleck et al., 1997; Verhoeven et al., 2009), visceral pain disorders (Moloney et al., 2016), anxiety (Faravelli et al., 2012), depression (Hammen, 2005; Mazure et al., 2000), and drug and alcohol dependence (Blaine and Sinha, 2017; Lemieux and al’Absi, 2016; Piazza and Le Moal, 1996).”

“We examined subregions of the mPFC and amygdala, which are implicated in both PTSD, AUD, and activated by predator odor (Asok et al., 2013, Edwards et al., 2013, Hwa et al., 2019).”

“As AUD is associated with elevated basal stress hormones [36] and hippocampal volume changes [37], we hypothesized that chronic alcohol intake in AUD could result in an unusual memory bias: enhanced memory for alcohol-related associations, but not items [12].”

“Furthermore, stress is a salient risk factor for relapse (Blaine and Sinha, 2017), suggesting treatments that target the HPA response may be efficacious in treating AUD.”

“As described in studies of various types of alcoholism, including chronic alcohol administration, withdrawal and binge models, HT7 stimulation alleviates depression and anxiety behaviors and alters the plasma CORT levels [16,34].”

“Growing evidence suggests that ABD in adolescence correlates with higher tonic levels of heart rate and cortisol, which indicate a hypersensitivity of the brain stress system (68).”

“The mechanisms underlying these relationships are complex and include noradrenergic,(9) corticotropin releasing factor (CRF)(10) and glucocorticoid receptor (GR) pathways.(11,12)”

“…stress-responsive systems such as corticotrophin-releasing factor, neuropeptide Y, and glucocorticoid receptor (Koob and Mason, 2016; Mantsch et al., 2016; Blaine and Sinha, 2017; Mason, 2017; Pomrenze et al., 2017; Robinson and Thiele, 2017; Spierling and Zorrilla, 2017; Tunstall et al., 2017).”

“Moreover, previous studies indicate that alterations in the HPA axis may facilitate the transition from mild-to-moderate alcohol drinking to AUD and may contribute to the risk of relapse (Koob, 2010; Blaine and Sinha, 2017).”

“Besides this, these brain regions regulate the hypothalamic-pituitary-adrenal (HPA) axis activity, which is also a critical mechanism contributing to protracted alcoholism.(15,16) Clinical and experimental studies in both humans and rodents have shown that”

“Monoamine activity in other brain regions that comprise parts of the limbic, motor, reward, and stress circuits remains less characterized, despite probable contributions to the motivation to consume alcohol or cognitive dysfunction related to alcohol ingestion (Blaine & Sinha, 2017).”

“Indeed, previous studies have posited that glucocorticoids and the HPA axis may have an important role for the development and chronicity for AUDs due to their connection with limbic and prefrontal cortex circuits (Blaine & Sinha, 2017).”

“, 2012; Becker, 2017), and heavy alcohol drinking causes adaptations in HPA axis function and stress-related brain systems and neurocircuitry (Stephens and Wand, 2012; Lu and Richardson, 2014; Blaine and Sinha, 2017; Weera and Gilpin, 2019).”

“At the clinical level, Blaine and Sinha (2017) review the role of *Corresponding author. harris@austin.utexas.edu (R.A. Harris).”