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).”

“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).”

“…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 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).”

“…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).”

“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 (…”

“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).”

“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).”

“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).”

“…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).”

“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).”

“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.”

“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).”

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

“…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).”

“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).”

“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…”

“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).”

“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).”

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

“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.”

“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).”

“…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).”

“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).”

“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…”

“…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.”

“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).”

“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.”

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

“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).”