Arginine vasopressin and adrenocorticotropin secretion in response to psychosocial stress is attenuated by ethanol in sons of alcohol-dependent fathers

Familial risk and environmental stress promote the development of alcohol dependence. We investigated whether a positive family history of alcoholism affects the neuroendocrine response to a standardized laboratory stress test in healthy subjects without alcohol use disorders. Twenty-four high-risk subjects with a paternal history of alcoholism (PHA) and 16 family history negative (FHN) controls were evaluated. Psychosocial stress was induced by having subjects deliver a 5-min speech and mental arithmetics in front of an audience on separate days, after drinking either placebo or ethanol (0.6 g/kg) in a randomized sequence. Adrenocorticotropin (ACTH) was measured in 10 plasma samples covering up to 75 min after the stress test. Plasma arginine vasopressin (AVP) was determined before the stressor, at the time of maximum ACTH secretion, and at 75 min after stress onset. The stress test induced a phasic increase in ACTH secretion. At the time of maximum ACTH, AVP was significantly increased in relation to baseline. Compared to placebo, alcohol administration significantly attenuated maximum ACTH concentration in PHA but not FHN subjects, and decreased AVP measured in the same samples in PHA but not FHN subjects. We conclude that activation of the hypothalamic-pituitary-adrenal system by psychosocial stress is accompanied by an increase in peripheral plasma AVP levels. Secretion of both ACTH and AVP suggest that alcohol attenuates the stress response selectively in PHA but not FHN subjects. This might imply some short-term positive alcohol effect in sons of alcoholics, but also constitute a mechanism by which their risk to develop alcohol use disorders is increased.     

Alcohol urge and plasma beta-endorphin change after alcohol challenge with naltrexone pretreatment in social drinkers

The authors have investigated the effect of naltrexone (NTX) on lowering the urge of alcohol drinking and the action mechanism of NTX. Fifteen healthy male social drinkers voluntarily participated. The experimental method was a double-blind, placebo-controlled cross-over design. To eliminate NTX effect, 1 week washout cross-over interval was taken. Subjects ingested NTX, 50 mg/day, or placebo for 1 week. Then, the alcohol (0.5 ml/kg) challenge test was done in the evening. Blood samples were taken immediately before drinking, at 20 min and at 60 min after alcohol drinking. Plasma beta-endorphin, plasma ACTH and serum cortisol levels were checked. Subjects completed self-report questionnaires such as the visual analog scales of drink urge and the alcohol sensation scales at regular intervals. In the case of NTX pretreatment, the subjects reported significantly (P=.013) less urge to drink alcohol on the self-reporting urge scales, especially at postdrinking 20 min and 60 min than placebo pretreatment. After alcohol challenge, the subjects reported significantly more dizziness (P=.015) in the case of NTX pretreatment, and reported less mood elevation trend, though not significant (P=.052). Basal plasma beta-endorphin levels were not different, but in the case of NTX pretreatment, the increasing degree of plasma beta-endorphin during 20 min after alcohol challenge was significantly (P=.039) higher than with placebo pretreatment. This results show that the NTX reduced the urge to drink alcohol with the mechanism of partially blocking the opioid positive reward system and partially mimicking the alcohol effect.     

Hypothalamic-pituitary-adrenocortical axis activity: a target of pharmacological anticraving treatment?

BACKGROUND: An association between the activity of the hypothalamic-pituitary-adrenocortical (HPA) axis and alcohol intake behavior is currently discussed. We examined the relationship between efficacy of pharmacological anticraving treatment and HPA axis activity in the relapse prevention treatment of alcoholism. METHODS: In 160 patients suffering from alcoholism, we measured plasma adrenocorticotropic hormone (ACTH) and cortisol during placebo-controlled relapse prevention treatment with naltrexone and/or acamprosate. RESULTS: In the placebo group, ACTH and cortisol decreased during early abstinence. Treatment with naltrexone and acamprosate prevented this course. Increased ACTH and cortisol during treatment was associated with a reduced risk of relapse. CONCLUSIONS: These findings suggest that heightened HPA responsiveness might contribute to relapse-preventing effects of anticraving compounds in alcoholism.     

Behavioral and EEG responses to alcohol in nonalcoholic men with a family history of alcoholism

1. 1. Behavioral and EEG responses were examined in nonalcoholic males with (FH+) and without (FH-) a family history of alcoholism following the consumption of a placebo and real beer.

2. 2. FH+ subjects were less confident of being able to resist another drink following consumption of the placebo and reported higher taste ratings and feeling more intoxicated following ethanol consumption than FH- subjects.

3. 3. Both groups showed increases in EEG alpha activity (9–12Hz) following alcohol consumption.4. Alpha activity was positively associated with desire to drink in the FH+ group before and after consumption, but was positively associated with perceived intoxication in the FH- group only after consumption.

Neurobiological effects of lumbar puncture stress in psychiatric patients and healthy volunteers

Several existing laboratory-based stress paradigms have significant shortcomings for assessing neurobiological correlates of stress in healthy volunteers and severely ill psychiatric patients. We have examined neuroendocrine effects of stress associated with the lumbar puncture (LP) procedure in drug-free depressed and schizophrenic patients and healthy volunteers. Healthy volunteers and depressed patients had significant stress-induced elevations in plasma levels of adrenocorticotropic hormone (ACTH), cortisol, and growth hormone associated with LP. In contrast, schizophrenic patients had no significant elevations in any of the neuroendocrine parameters. Depressed patients' cerebrospinal fluid norepinephrine levels were negatively correlated with stress-induced activation of the hypothalamic-pituitary-adrenal axis. In addition, depressed patients' basal plasma cortisol levels were strongly predictive of stress-related elevations in ACTH, cortisol, and growth hormone. Furthermore, stress-induced changes in schizophrenic patients' cortisol and ACTH levels were not correlated.     

Long-term habituation of brain evoked potential responses and pituitary-adrenal secretion with repeated (placebo) testing

To study whether changes in late auditory evoked potentials (AF-Ps) and/or in stress-sensitive hormones of the hypothalamic—pituitary-adrenal (HPA) system take place between a first and a second placebo experiment and if so, whether these changes are possibly related to each other, we conducted two identical placebo sessions (2 ml 0.9% saline) and one cortisol session (50 mg) with 10 subjects on three different days. Plasma cortisol concentrations were significantly higher at the beginning of the first placebo experiment than the second, with a concordant decrease of plasma adrenocorticotropin hormone (ACTH) concentrations. In the AEP domain, a consistently lower P2 amplitude was observed in the first session. Since the change in late auditory processing could not be demonstrated after exogenous administration of cortisol, a direct mediation through an elevation of plasma cortisol concentrations or indirect mediation through a decrease of plasma ACTH concentrations seems unlikely. We rather propose that other stress-sensitive mechanisms, such as CCK, might account for the novelty-induced P2 amplitude lowering.     

Plasma cortisol levels following ethanol in sons of alcoholics and controls

We used the pattern of change in plasma cortisol level following ethanol challenges to help characterize differences in response to alcohol in sons of alcoholics and controls. Thirty healthy, drinking young adult sons of alcoholics were matched with 30 sons of nonalcoholics on demography, drug use, and alcohol use histories. Each was tested on three occasions, when he received, in random order, placebo, 0.75 mL/kg of ethanol, and 1.1 mL/kg of ethanol. Subsequent blood samples for cortisol determinations were obtained every 30 minutes over the next four hours. The sons of alcoholics, at higher risk for the future development of alcoholism, demonstrated lower cortisol levels after drinking. The data are consistent with our prior measures of self-reported feelings of intoxication and family group differences in ethanol-induced decrements in performance.     

Effects of childhood trauma on HPA-axis reactivity in women free of lifetime psychopathology

Exposure to childhood trauma may induce persistent changes in Hypothalamic-Pituitary-Adrenal (HPA)-axis functioning even in the absence of current psychopathology. Because previous studies did not systematically exclude subjects with lifetime psychiatric morbidity, prevalent psychopathology may have confounded the association. In this study we investigated whether women exposed to childhood trauma, but without a history of psychiatric disorders, show alterations in HPA-axis functioning. We included 10 women exposed to significant childhood trauma and 12 non-exposed women. All women were between 29 and 64 years old, mentally and physically healthy, and without current or lifetime psychopathology. HPA-axis functioning was assessed as 1) basal activity with salivary cortisol patterns over 8 time points on two consecutive sampling days and 2) plasma cortisol and adrenocorticotropic hormone (ACTH) reactivity over 7 time points after the combined dexamethasone/corticotropin-releasing hormone (dex/CRH) challenge test. Basal salivary cortisol output did not differ between trauma-exposed compared to non-exposed women. Significantly blunted plasma cortisol and ACTH responses in response to dex/CRH administration were found in the trauma-exposed compared to the non-exposed women (F(1,20) = 5.08, p = 0.04 and F(1,20) = 5.23, p = 0.03 respectively). Adjusting for age, body mass index (BMI), oral contraceptive use, and menopausal status, somewhat weakened the associations for cortisol as well as ACTH (F(1,16) = 3.30, p = 0.09) and F(1,16) = 2.17, p = 0.16 respectively), but for cortisol absolute differences in point estimates were largely unaffected. Although basal cortisol patterns were similar in the two groups, exposure to childhood trauma seemed to be related to a blunted HPA-axis reactivity in women who were free of current or lifetime psychopathology.     

Interindividual differences in stress sensitivity: basal and stress-induced cortisol levels differentially predict neural vigilance processing under stress

Stress exposure is known to precipitate psychological disorders. However, large differences exist in how individuals respond to stressful situations. A major marker for stress sensitivity is hypothalamus–pituitary–adrenal (HPA)-axis function. Here, we studied how interindividual variance in both basal cortisol levels and stress-induced cortisol responses predicts differences in neural vigilance processing during stress exposure. Implementing a randomized, counterbalanced, crossover design, 120 healthy male participants were exposed to a stress-induction and control procedure, followed by an emotional perception task (viewing fearful and happy faces) during fMRI scanning. Stress sensitivity was assessed using physiological (salivary cortisol levels) and psychological measures (trait questionnaires). High stress-induced cortisol responses were associated with increased stress sensitivity as assessed by psychological questionnaires, a stronger stress-induced increase in medial temporal activity and greater differential amygdala responses to fearful as opposed to happy faces under control conditions. In contrast, high basal cortisol levels were related to relative stress resilience as reflected by higher extraversion scores, a lower stress-induced increase in amygdala activity and enhanced differential processing of fearful compared with happy faces under stress. These findings seem to reflect a critical role for HPA-axis signaling in stress coping; higher basal levels indicate stress resilience, whereas higher cortisol responsivity to stress might facilitate recovery in those individuals prone to react sensitively to stress.     

Personality of panic disorder alcohol abusers

Seventeen (28%) of 61 panic disorder patients in a drug treatment study were retrospectively found to have a history of alcoholism (none had abused alcohol in the past year), More men than women had a history of alcohol abuse (p less than .03). Alcohol patients were less independent and less able to recognize appropriate social cues on personality testing. There was significant improvement in general anxiety for the drug treatment and nonalcoholic placebo group but not for the alcohol placebo group. This indicates a superior response to supportive therapy for general anxiety in the placebo group without an alcohol abuse history compared with the placebo group with an alcohol abuse history.     

Electroencephalographic activity and plasma ACTH during ethanol-induced euphoria

Covariance of brain electrical activity (EEG), plasma adrenocorticotrophic hormone (ACTH) and cortisol levels, and mood states were determined for healthy adult men during the first 2 hr after ingestion of ethanol or ethanol placebo under controlled double-blind conditions. Analysis of integrated plasma ACTH and cortisol levels at 5-min intervals, EEG power spectral analysis during consecutive 2-min epochs, and continuous assessment of mood states with a nonverbal instrumental device were carried out during the ascending phase of the blood ethanol curve. Ethanol induced rapid changes in brain electrical activity and plasma ACTH levels that were significantly correlated with subjective perception of changes in mood. The paroxysmal short epochs of euphoria associated with electroencephalographic and ACTH responses during the ascending phase of the blood ethanol curve may reflect physiological concomitants of pharmacological and behavioral reinforcers that enhance risk for perpetuation of drinking and alcohol abuse.     

The social complications of chronic alcohol abuse: relative influence of family history and severity of alcohol dependence

Alcoholics with a family history of the disease are said to present more severe consequences than alcoholics without such a history. This study examined the frequency distribution of severe alcohol dependence and police arrests for public drunkenness across samples of alcoholics with (n = 77) and without (n = 37) a family history of alcoholism. Both the percentage of subjects presenting severe dependence and the history of police arrests were greater in the positive family history group, but these differences did not reach conventional levels of statistical significance. However, results of logistic regression analyses demonstrate that male sex, younger age and, above all, severity of alcohol dependence, are better correlates of the occurrence of police arrests than is the subject's family history of alcoholism. The picture presented by this sample of outpatient alcoholics appears to qualify some currently held assumptions of the influence of family history on the phenomenology of alcoholism.     

Hypothalamic-pituitary-adrenal system adaptation to detoxification in alcohol-dependent patients is affected by family history of alcoholism.

BACKGROUND: Alcohol withdrawal profoundly affects the hypothalamic-pituitary-adrenocortical (HPA) system. We investigated whether a family history of alcoholism modulates HPA response to pharmacologic intervention during detoxification in alcohol-dependent patients. METHODS: Sixteen family history negative (FH-N) and 19 family history positive (FH-P) alcohol-dependent patients were admitted for withdrawal. All 35 patients were investigated 1 week after remission of withdrawal symptoms; 17 patients were also tested during acute withdrawal. Dexamethasone 1.5 mg was given orally at 11 PM, followed by 100 microg corticotropin-releasing hormone (hCRH) administered intravenously at 3 PM the following day. Plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations were determined at 0, 30, 45, 60, and 75 min after CRH. RESULTS: During withdrawal, cortisol but not ACTH secretion was increased in patients compared with 19 control subjects matched for age and gender. After withdrawal, cortisol was normal in FH-P but still increased in FH-N patients versus control subjects, and ACTH was marginally decreased in FH-P patients only. Both hormones were increased in FH-N versus FH-P patients. CONCLUSIONS: Recovery from alcohol withdrawal-induced impairment of HPA system regulation occurs earlier in FH-P than FH-N patients, indicating that the efficacy of central neuroadaptation to this ethanol-related stimulus may be related to genetic factors.     

Endocrine response to surgical stress and postoperative confusion in depressed patients with alcohol abuse

Both alcohol drinking and depression are risk factors for postoperative confusion and are associated with alteration of pituitary-adrenal function. We investigated the incidence of postoperative confusion, plasma cortisol and ACTH response to surgical stress in depressed patients with alcohol abuse. We studied sixty depressed patients with and without alcohol abuse who underwent abdominal surgery. Postoperative confusion occurred in 4 of 30 patients (13%) in depressed patients without alcohol abuse, 10 of 30 patients (33%) in depressed patients with alcohol abuse. Plasma cortisol concentrations (27.2 +/- 7.0, 28.3 +/- 8.2, 29.2 +/- 4.1, 28.0 +/- 6.3 and 27.9 +/- 5.7 microg dl(-1)) 15, 60 min after the skin incision, 60 min after the end of surgery, the next day and the third day after surgery in depressed patients with alcohol abuse were significantly higher than that (20.1 +/- 6.4, 21.7 +/- 9.6, 22.3 +/- 8.0, 21.9 +/- 6.7 and 20.3 +/- 5.4 microg dl(-1)) in depressed patients without alcohol abuse. In depressed patients with alcohol abuse, plasma cortisol concentrations (34.9 +/- 7.1, 33.2 +/- 5.8 and 33.4 +/- 5.5 microg dl(-1)) 60 min after the end of surgery, the next day and third day after surgery in postoperatively confused depressed patients were significantly higher than those (26.4 +/- 6.3, 25.4 +/- 5.0 and 25.2 +/- 4.9 microg dl(-1)) of nonconfused depressed patients. In conclusion, the incidence of postoperative confusion was significantly higher in depressed patients with alcohol abuse than in depressed patients without alcohol abuse. Increased plasma cortisol concentrations after surgery were associated with postoperative confusion in depressed patients with alcohol abuse.     

Associations of phenylthiocarbamide tasting to alcohol problems and family history of alcoholism differ by gender

Past research associating phenylthiocarbamide/propylthiouracil (PTC/PROP) taste status with alcoholism has produced equivocal results. Some have found higher proportions of nontasters among those with a family history of alcoholism than controls, whereas others have not. The purpose of this study was to investigate the relationship between PTC taste status, alcohol problems, and family history of alcoholism. A total of 244 undergraduate students participated in this study, with a gender distribution of 75% female and 25% male. We found support for our hypothesis that male supertasters would report fewer problems with alcohol and a less significant family history of alcoholism. Interestingly, we also found that female supertasters had a greater family history of alcoholism and more current problems associated with alcohol use. Implications for the genetic link between PTC taste status and alcoholism are discussed.     

Family history of alcoholism influences naltrexone-induced reduction in alcohol drinking.

BACKGROUND: The purpose of this study was to examine the interactive effects of family history of alcoholism (FH+, FH-) and naltrexone dose (0, 50, 100 mg/day) on alcohol drinking. METHODS: Ninety-two, non-treatment-seeking alcohol-dependent participants received naltrexone daily for 6 days. On the 6th day, they participated in a laboratory paradigm involving exposure to a priming dose of alcohol followed by a 2-hour drinking period in which they made choices between consuming alcoholic drinks and receiving money. RESULTS: Total number of drinks consumed during the drinking period was significantly decreased by the 100-mg dose of naltrexone in FH+ drinkers. Secondary analyses in male drinkers (n = 70) indicated that 100 mg of naltrexone significantly decreased drinking in FH+ participants and increased drinking in FH- drinkers. CONCLUSIONS: These results suggest that family history of alcoholism might be a significant clinical predictor of response to naltrexone and that FH+ men are more likely to benefit from naltrexone therapy for alcohol drinking.     

Glucocorticoid feedback sensitivity and adrenocortical responsiveness in posttraumatic stress disorder.

BACKGROUND: Decreased basal cortisol levels have been reported in individuals with posttraumatic stress disorder (PTSD). There is evidence for enhanced negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) axis in PTSD, which could account for this, but other possible mechanisms have not been ruled out. We examined the HPA axis employing a metyrapone-cortisol infusion protocol designed to study negative feedback sensitivity. METHODS: Vietnam combat trauma-exposed subjects met DSM-IV criteria for PTSD. Exclusion criteria included substance abuse and most medications. Endogenous feedback inhibition was removed by blocking cortisol synthesis with oral metyrapone and reintroduced by intravenous infusion of cortisol. In a placebo condition, subjects received oral placebo and normal saline infusion. Serial blood samples drawn over 4 hours were assayed for adrenocorticotrophic hormone (ACTH), cortisol, and 11-deoxycortisol. Selected samples were assayed for cortisol binding globulin (CBG) and dehydroepiandrosterone (DHEA). RESULTS: Basal plasma cortisol was significantly decreased in PTSD subjects (n = 13) compared with control subjects (n = 16). No significant difference in the ACTH response to cortisol infusion following metyrapone was observed; however 11-deoxycortisol was significantly decreased in PTSD subjects. In addition, CBG was significantly increased in PTSD subjects, and DHEA was significantly decreased in both PTSD and combat-exposed control subjects. CONCLUSIONS: These observations suggest decreased adrenocortical responsiveness may be an additional or alternative mechanism accounting for low cortisol in PTSD.     

Effects of Alzheimer's disease and gender on the hypothalamic-pituitary-adrenal axis response to lumbar puncture stress.

Differences in hypothalamic-pituitary-adrenal (HPA) axis responsiveness to lumbar puncture (LP) stress were studied in normal elderly subjects and Alzheimer's disease (AD) patients of both genders. Elderly normal subjects had larger peak cortisol and ACTH responses than AD patients. These results contrast with some previous reports of increased HPA-axis responsivity associated with AD and suggest that AD-related changes in HPA responsiveness depend on the type of stressor involved and are mediated 'upstream' to the final common pathway to ACTH secretion. HPA-axis responsiveness also differed by gender, with higher peaks and prolonged elevations in elderly female subjects than in elderly males.     

Brain-specific inactivation of the Crhr1 gene inhibits post-dependent and stress-induced alcohol intake, but does not affect relapse-like drinking

Corticotropin-releasing hormone (CRH) and its receptor, CRH receptor-1 (CRHR1), have a key role in alcoholism. Especially, post-dependent and stress-induced alcohol intake involve CRH/CRHR1 signaling within extra-hypothalamic structures, but a contribution of the hypothalamic-pituitary-adrenal (HPA) axis activity might be involved as well. Here we examined the role of CRHR1 in various drinking conditions in relation to HPA and extra-HPA sites, and studied relapse-like drinking behavior in the alcohol deprivation model (ADE). To dissect CRH/CRHR1 extra-HPA and HPA signaling on a molecular level, a conditional brain-specific Crhr1-knockout (Crhr1(NestinCre)) and a global knockout mouse line were studied for basal alcohol drinking, stress-induced alcohol consumption, deprivation-induced intake, and escalated alcohol consumption in the post-dependent state. In a second set of experiments, we tested CRHR1 antagonists in the ADE model. Stress-induced augmentation of alcohol intake was lower in Crhr1(NestinCre) mice as compared with control animals. Crhr1(NestinCre) mice were also resistant to escalation of alcohol intake in the post-dependent state. Contrarily, global Crhr1 knockouts showed enhanced stress-induced alcohol consumption and a more pronounced escalation of intake in the post-dependent state than their control littermates. Basal intake and deprivation-induced intake were unaltered in both knockout models when compared with their respective controls. In line with these findings, CRHR1 antagonists did not affect relapse-like drinking after a deprivation period in rats. We conclude that CRH/CRHR1 extra-HPA and HPA signaling may have opposing effects on stress-related alcohol consumption. CRHR1 does not have a role in basal alcohol intake or relapse-like drinking situations with a low stress load.     

The relationships of historically defined subtypes of depression to ACTH and cortisol levels in depression: preliminary study

A family history of depression (but no alcoholism), a history of bipolarity, and a history of nonsuppressor status on the Dexamethasone Suppression Test (DST) have all been positively associated with each other in previous studies. We divided depressives into three mutually exclusive groups, using the three historical parameters described above. Group A included those who were nonsuppressors at index. Group B included normal suppressors at index who met one of the following three criteria: (1) past history of a nonsuppressing DST, (2) past history of a mania, and (3) family history of depression (but no alcoholism). The remaining suppressors at index made up Group C. We found that Groups A and B show a phase advance (an earlier nadir) in the predexamethasone circadian curve for cortisol. Adrenocorticotrophic hormone (ACTH) varies in part (but not solely) with cortisol and may separate the groups.