Variable dose naltrexone-induced hypothalamic-pituitary-adrenal stimulation in abstinent alcoholics: a preliminary study

Opiate antagonists have been found to stimulate the hypothalamic-pituitary-adrenal axis. However, despite established usefulness in the management of alcoholism, systematic, oral dose-titrated natrexone-induced hypothalamic-pituitary-adrenal stimulation has never been studied in alcoholics. Six patients (5 males, 1 female) with DSM-IV alcohol dependence, who were at least 4 weeks abstinent from any alcohol [mean 55 days (+/-SE 7.5)], were given four challenges of oral naltrexone (0, 25, 50, and 100 mg) in a randomized order at least 3 days apart, after an overnight fast. Naltrexone was administered at 9 AM; serum ACTH, cortisol, and prolactin were measured at time 0 and at 9 time points over the next 4 hr. Subjects also filled out a side effect questionnaire and an alcohol urge questionnaire. Physiological measurements of blood pressure and pulse rate were taken at the same time points. Repeated-measures ANOVA of the changes in serum ACTHs over time revealed a significant effect of drug (placebo vs. any dose of naltrexone) (p < 0.05). Post-hoc analysis revealed a significant difference between placebo and the 25 mg dose (p < 0.01), the 50 mg dose (p < 0.01), but no significance between the placebo and the 100 mg dose (p = 0.1). A repeated-measures ANOVA of the changes in serum cortisols over time revealed a significant effect of drug (p < 0.01). Post-hoc analysis revealed a significant difference between placebo and the 25 mg dose (p < 0.01), between placebo and the 50 mg dose (p < 0.05), and placebo and the 100 mg dose (p < 0.01). There was a significant between dose difference in pulse rate changes over baseline (p < 0.01), and post-hoc analysis revealed a significant diminution in pulse rate at the 100 mg dose relative to placebo (p < 0.001), and to the other doses. There were no significant differences in reported side effects, alcohol urge questionnaire scores, or in other physiological measurements between doses. These data suggest a significant rise in ACTH and cortisol in response to naltrexone in alcoholics compared with placebo, with no differences between 25 mg, 50 mg, and 100 mg doses, and a significant diminution in pulse rate responses at the 100 mg dose.     

Blunted stress cortisol response in abstinent alcoholic and polysubstance-abusing men

BACKGROUND: This study tested cortisol responses to a psychological stressor in controls (CT) versus patients who were diagnosed as alcohol dependent (AD) or alcohol and stimulant dependent (ADSD) by DSM-IV criteria and who were abstinent for 3 to 4 weeks from alcohol and illicit drugs. Alcohol increases cortisol secretion acutely and during withdrawal. However, there is little information about abnormalities of hypothalamic-pituitary-adrenocortical (HPA) reactivity in recovering alcoholics. METHODS: Accordingly, we tested HPA function in the laboratory between 7:00 and 9:30 AM on control versus stress days. Stress consisted of a 20-min public speaking challenge with preparation and delivery of two short speeches, ostensibly evaluated for quality of delivery, whereas control involved relaxing for the same period. Cortisol was measured in saliva collected at baseline, stress or control, and recovery period, and also at home at 9:00 PM on one of the two days. RESULTS: The three groups did not differ in diurnal patterns of cortisol secretion on the rest day and 9:00 PM sample, which indicated that AD and ADSD patients had intact diurnal HPA regulation at rest. During speech stress, the CT subjects showed the expected cortisol increase (p < 0.0001), whereas neither AD nor ADSD patients responded significantly. Cortisol values were not accounted for by covariates such as depression, posttraumatic stress disorder, glucose metabolism, or anthropometric or demographic characteristics. CONCLUSIONS: The apparent stress hyporesponsiveness of the AD and ADSD patients suggests a persistent disruption of HPA function, perhaps due to incomplete recovery from prior abuse, or to a preexisting alteration in neural systems that regulate HPA responses to stress.     

Hypothalamic function in response to 2-deoxy-D-glucose in long-term abstinent alcoholics

BACKGROUND: The body adapts to diverse stressful stimuli with a response characterized by activation of the hypothalamic-pituitary-adrenal (HPA) axis. Chronic alcohol consumption can cause changes in the function of this neuroendocrine system. Although many studies have examined this phenomenon in drinking and recently sober alcoholics, few studies have examined HPA axis function in long-term sober alcoholics. METHODS: To characterize HPA axis function in long-term sober alcoholics, we used a challenge paradigm with 2-deoxy-d-glucose (2-DG). An infusion of 2-DG (a nonmetabolizable glucose analog) induces a well-characterized stress response. In a previous study, our laboratory found an exaggerated corticotropin and cortisol response in alcoholics abstinent 3 weeks; in this investigation we compared the effects of an infusion of 2-DG on 19 healthy volunteers and 20 community-living alcoholics who had been abstinent more than 6 months. RESULTS: In contrast to the previous study, long-term sober alcoholics did not have an exaggerated corticotropin and cortisol response after 2-DG. CONCLUSIONS: Previously observed abnormalities in cortisol regulation in 3-week-sober alcoholics may be related to the acute effects of recent alcohol consumption and withdrawal. Future investigations into the metabolic function of alcoholics, particularly investigations involving the HPA system, should consider the possibility that normalization may not occur until long-term abstinence has been achieved.     

Cognitive performance in long-term abstinent elderly alcoholics

BACKGROUND: To date, there is a wealth of literature describing the deleterious effects of active alcoholism on cognitive function. There is also a growing body of literature on the extent of cognitive recovery that can occur with abstinence. However, there is still a dearth of published findings on cognitive functioning in very long-term abstinence alcoholics, especially in the elderly population. METHODS: The current study examines 91 elderly abstinent alcoholics (EAA) (49 men and 42 women) with an average age of 67.3 years, abstinent for an average of 14.8 years (range 0.5 to 45 years), and age and gender comparable light/nondrinking controls. The EAA group was divided into 3 subgroups: individuals that attained abstinence before age 50 years, between the ages 50 and 60 years, and after age 60 years. Attention, verbal fluency, abstraction/cognitive flexibility, psychomotor, immediate memory, delayed memory, reaction time, spatial processing, and auditory working memory were assessed. The AMNART and cranium size were used as estimates of brain reserve capacity, and the association of all variables with alcohol use measures was examined. RESULTS: Overall, the EAA groups performed comparably to controls on the assessments of cognitive function. Only the abstinent in group before 50 years of age performed worse than controls, and this was only in the domain of auditory working memory. EAAs had larger craniums than their controls. This effect was strongest for those who drank the longest and had the shortest abstinence. Such individuals also performed better cognitively. CONCLUSIONS: Our data showed that elderly alcoholics that drank late into life, but with at least 6 months abstinence can exhibit normal cognitive functioning. Selective survivorship and selection bias probably play a part in these findings. Cognitively healthier alcoholics, with more brain reserve capacity, may be more likely to live into their 60s, 70s, or 80s of age with relatively intact cognition, and to volunteer for studies such as this. Our results do not imply that all elderly alcoholics with long-term abstinence will attain normal cognition.     

Leptin and cellular and innate immunity in abstinent alcoholics and controls

BACKGROUND: Basic studies indicate that in vitro and in vivo doses of leptin modulate cellular immune responses. Given evidence that concentrations of leptin are altered in alcoholics who also show immune abnormalities, this study examined the relationships between circulating levels of leptin and markers of cellular and innate immunity. METHODS: Circulating levels of leptin, natural killer cell (NK) activity, interleukin-2 (IL-2)-stimulated NK activity, and concanavalin A-stimulated production of IL-2, IL-6, IL-10, and IL-12 were compared between abstinent DSM-IV alcohol-dependent men (n = 27) and age- and gender-matched controls (n = 34). RESULTS: As compared with controls, alcoholics showed lower NK activity (p < 0.01) and a trend for lower levels of leptin (p = 0.055). In the total sample, leptin predicted NK activity (beta = 0.33; p < 0.05) after controlling for the confounding influence of body mass index, alcohol intake, and smoking. Leptin was not correlated with any of the cytokine measures. To examine whether the effects of leptin were mediated by its direct action on NK, additional studies examined in vitro effects of leptin on NK activity in healthy volunteers (n = 10); leptin doses (0.1, 1, and 10 nM) yielded levels of NK activity comparable to those with media alone. CONCLUSIONS: These data show that circulating levels of leptin are associated with NK activity in humans and suggest that abnormal in vivo concentrations of leptin may contribute to the declines of NK activity in alcoholics who are at risk for infectious diseases.     

Children of alcoholics exhibit attenuated cognitive impairment during an ethanol challenge

In an attempt to identify markers potentially related to the development of problem drinking, we examined cognitive functioning in children of alcoholics (COAs) and children of nonalcoholics, both while sober and after consuming 0.85 ml/kg of ethanol. Consonant with previous research indicating that COAs exhibit less intense responses to alcohol, we predicted that COAs would experience attenuated cognitive deficits while intoxicated. Male (n = 71) and female (n = 29) college students completed tests of contextual and rote memory recall in a repeated-measures design. Findings indicated that intoxication impaired both memory and attentional capacities, and that COAs exhibited attenuated cognitive deficits relative to children of nonalcoholics. Results were consistent with previous research demonstrating attenuated responses to alcohol in COAs. Potential mechanisms for the pathogenesis of problem drinking are discussed.     

Reduced cortical thickness in abstinent alcoholics and association with alcoholic behavior

Background: Chronic misuse of alcohol results in widespread damage to the brain. Prior morphometric studies have examined cortical atrophy in individuals with alcoholism; however, no previous studies have examined alcohol‐associated atrophy using cortical thickness measurements to obtain regional mapping of tissue loss across the full cortical surface. Methods: We compared cortical thickness measures from 31 abstinent individuals with a history of prior alcohol abuse to 34 healthy nonalcoholic control participants (total sample size = 65). Cortical surface models were created from high‐resolution T1‐weighted images, and cortical thickness was then estimated as the distance between the gray matter/white matter boundary and the outer cortical surface. Results: Abstinent alcoholics showed reduced whole‐brain thickness as compared to nonalcoholic participants. Decreases in thickness were found bilaterally in (i) superior frontal, (ii) precentral, (iii) postcentral, (iv) middle frontal, (v) middle/superior temporal, (vi) middle temporal, and (vii) lateral occipital cortical regions. Decreased cortical thickness in the alcoholic group was associated with severity of alcohol abuse. Conclusions: These findings demonstrate widespread reduction in cortical thickness as a consequence of chronic alcoholism, with most severe reductions in frontal and temporal brain regions.     

Increased distractibility by task-irrelevant sound changes in abstinent alcoholics

Background: Chronic alcoholism is accompanied by "frontal" neuropsychological deficits that include an inability to maintain focus of attention. This might be associated with pronounced involuntary attention shifting to task-irrelevant stimulus changes and, thereafter, an impaired reorienting to the relevant task. The neural abnormalities that underlie such deficits in alcoholics were explored with event-related potential (ERP) components that disclosed different phases of detection and orienting to stimulus changes.
Methods: Twenty consecutive abstinent male alcoholics (DSM-IV) and 20 age-matched male controls (healthy social drinkers) were instructed to discriminate equiprobable 100 and 200 msec tones in a reaction-time task (RT) and to ignore occasional, either slight (7%) or wide (70%), frequency changes (hypothesized to increase RT) during an ERP measurement.
Results: In the alcoholics, we found pronounced distractibility, evidenced by a RT lag ( p < 0.01) caused by deviants, that correlated (Spearman ρ= 0.5) with a significantly enhanced ( p < 0.01) amplitude of mismatch negativity (MMN) to deviants. Significantly increased RT lag for trials subsequent to deviants (slight p < 0.001, wide p < 0.05) in the alcoholics suggested impaired reorienting to the relevant task. The MMN enhancement also predicted poorer hit rates in the alcoholics (Spearman ρ= 0.6–0.7). Both the MMN enhancement and pronounced distractibility correlated (Spearman ρ= 0.4) with an early onset of alcoholism.
Conclusions: Attentional deficits in the abstinent alcoholics were indicated by the increased distractibility by irrelevant sound changes. The MMN enhancement suggested that this reflects impaired neural inhibition of involuntary attention shifting, being most pronounced in early-onset alcoholics.     

Visual P300s in long-term abstinent chronic alcoholics

BACKGROUND: Evidence of reduced P3b amplitudes in chronic alcoholics and individuals at risk for developing alcoholism suggest that the P3b may be an endophenotypic marker for alcoholism. If this is the case, then long-term abstinent alcoholics (LTAAs) should exhibit reduced P3b amplitudes. Thus far, P3b studies on chronic alcoholics have focused primarily on samples with relatively short-term abstinence (less than 15 months). This study examines the amplitude and latency of the P3b and P3a event-related brain electrical components in LTAAs compared with normal controls (NCs) and whether these measures are related to alcohol use and other subject variables. METHODS: Electroencephalographs (EEGs) were recorded on 48 LTAAs (mean abstinence=6.7 years) compared with 48 age-matched and gender-matched NCs during a visual P300 experiment consisting of standard, target, and rare nontarget conditions. This paradigm elicited the P3b (target condition) and the P3a (rare nontarget condition) components. RESULTS: Long-term abstinent alcoholics had reduced P3b amplitudes and increased P3b latencies in comparison with NCs. Long-term abstinent alcoholics also exhibited delayed P3a components, but no P3a amplitude reductions. Alcohol use variables, a family history of alcohol problems, and the duration of alcohol abstinence were not associated with any amplitude or latency variables. CONCLUSIONS: Even after very prolonged abstinence, reduced P3b amplitudes are present in chronic alcoholics and are not associated with any family history or alcohol use variables. These results provide equivocal support for reduced P3b amplitude being an endophenotypic marker for alcoholism, but are also consistent with P3b being affected by a threshold of alcohol abuse, with the effect not resolving over long periods of abstinence.     

Effect of Cigarette Smoking on ACTH/Cortisol Secretion in Alcoholics After Short- and Medium-Term Abstinence

BACKGROUND: To gain a better insight into the alterations of the hypothalamic-pituitary-adrenal axis in alcoholism, we evaluated the ACTH response to nicotine inhaled from cigarette smoking (two nonfilter cigarettes in succession within 10 min) in nine nonalcoholic men and nine age- and weight-matched alcoholic men who had been addicted to alcohol for at least 8 years. All subjects were regular cigarette smokers. METHODS: Alcoholic men were tested after 2 weeks of abstinence, when the possible interferences because of alcohol assumption or the acute withdrawal period had completely ceased, and again after 12 weeks of abstinence. RESULTS: At both 2 and 12 weeks of abstinence, basal plasma ACTH and cortisol levels were not significantly different in the alcoholic men from those observed in the control group. In the control group subjects, cigarette smoking induced a striking increase in the circulating concentrations of ACTH and cortisol, with peak responses 1.4 and 1.5 times higher than baseline at 20 and 30 min, respectively. In contrast, no significant ACTH/cortisol increase was observed in alcoholic subjects at any time after cigarette smoking in any test. CONCLUSION: These data suggest that alterations of nicotinic cholinergic transmission occur in the control of ACTH secretion in the alcoholic men, providing further evidence of modification of the hypothalamic-pituitary-adrenal axis in alcoholism.     

Preserved vasopressin response to osmostimulation despite decreased basal vasopressin levels in long-term abstinent alcoholics

BACKGROUND: Basal arginine vasopressin (AVP) plasma levels in alcoholic patients are persistently decreased over months of controlled alcohol abstinence. As a potential explanation of this phenomenon, a reduction of AVP immunoreactive neurons was described in the hypothalamus of alcohol-dependent humans and rodents. This study was therefore designed to examine whether long-term abstinent alcoholics have a compromised response of AVP to osmostimulation. METHODS: Fifteen male alcoholics, aged 42 +/- 2 years, were examined (1) over 12 months of strictly controlled abstinence (longitudinal study) and (2) during an osmostimulation test (5% NaCl infusion at 0.06 ml/kg/min over 2 hr) and were compared with 15 healthy male subjects, aged 41 +/- 2 years. AVP and routine laboratory parameters, including electrolytes and osmolality, were measured. RESULTS: Starting from lower basal concentrations, alcoholics showed increases similar to those of controls in AVP and plasma osmolality after osmostimulation. The first sensation of thirst was announced significantly later by alcoholics than by controls. Twenty-hour-posttest urine volume and sodium excretion were reduced in alcoholics compared with controls. CONCLUSIONS: Despite their persistently decreased basal AVP plasma levels, long-term abstinent alcoholics have a well preserved AVP response to osmostimulation. This finding indicates a peripheral suppression of AVP levels that is most likely due to a regulatory set-point shift toward hypotonic hyperhydration, rather than to a reduced central capacity of AVP secretion.     

Persistent alterations of vasopressin and N-terminal proatrial natriuretic peptide plasma levels in long-term abstinent alcoholics

BACKGROUND: During alcohol withdrawal and early abstinence, severe alterations of electrolyte and water homeostasis and their regulating hormones are well recognized. Almost nothing is known about regeneration of these functions with long-term abstinence. This cohort study was designed to monitor determinants of electrolyte and water balance over 280 days of abstinence in alcohol-dependent men compared with healthy controls. METHODS: Vasopressin (AVP), N-terminal proatrial natriuretic peptide, aldosterone, angiotensin II, and electrolytes, together with major parameters of kidney and liver function, were monitored in 35 male alcoholics aged 44 +/- 8 years. Of these, 21 could be followed up to 280 days of strictly controlled abstinence due to their participation in the Outpatient Long-Term Intensive Therapy for Alcoholics. The control group comprised 20 healthy male volunteers aged 39 +/- 7 years. RESULTS: Basal AVP levels were found to be suppressed over the whole study period. In contrast, N-terminal proatrial natriuretic peptide remained increased over all 280 days. No persistent alterations were found for aldosterone or angiotensin II. Sodium and potassium in plasma and urine returned to normal within a few weeks. Creatinine clearance, urea nitrogen in plasma and urine, urinary osmolality, hematocrit, and hemoglobin remained low as compared with controls over the entire study. CONCLUSIONS: Chronic alcohol abuse causes severe and persistent alterations in the hormonal regulatory systems of electrolyte and water balance. The suppressed basal secretion of AVP may reflect a dysregulation in the brain that influences the hypothalamic-pituitary-adrenal axis function, mood, memory, addiction behavior, and craving during alcohol abstinence. These findings may provide a ground for future therapeutic approaches to stable abstinence.     

Adrenocorticotropic hormone/cortisol response to physical exercise in abstinent alcoholic patients

BACKGROUND: Alterations in the hypothalamic-pituitary-adrenal (HPA) axis in alcoholic patients have been reported in various experimental conditions. METHODS: To establish whether alcoholism affects the HPA axis activation during physical exercise, 10 recent abstinent alcoholic patients (age range: 33-45 years; duration of alcohol dependence: range 4-6 years) were tested by exercising on a bicycle ergometer. Ten age-matched healthy nonalcoholic men participated as controls. The workload was gradually increased at 3-minute intervals until exhaustion and lasted about 15 minutes for all subjects. Alcoholic patients were tested at 3 time points, at 4, 6, and 8 weeks after alcohol withdrawal, whereas controls were tested only once. Main outcome measurements were circulating levels of adrenocorticotropic hormone (ACTH) and cortisol and physiological variables during physical exercise [heart rate, blood pressure, ventilation, frequency of breathing, tidal volume, oxygen consumption (VO2), carbon oxide production (VCO2), and respiratory exchange ratio (R)]. RESULTS: Similar basal and exercise-induced changes in physiological variables were observed in controls and alcoholic patients in all tests. Basal levels of ACTH and cortisol were similar in all tests performed on alcoholic patients and on normal controls. In normal subjects, exercise induced a significant increase in plasma ACTH and serum cortisol levels, with peak levels at 20 minutes for ACTH (84% higher than baseline) and at 30 minutes for cortisol (70% higher than baseline). After 4 weeks of abstinence, slight but not significant ACTH/cortisol responses to physical exercise were observed in alcoholic patients (mean peaks were 10 and 18% higher than baseline, respectively, for ACTH and cortisol). By contrast, when the exercise test was repeated after 6 weeks abstinence, ACTH/cortisol levels rose significantly versus baseline (mean peak levels of ACTH and cortisol were 48 and 38% higher than baseline, respectively, for ACTH and cortisol). However, the hormonal responses were significantly lower than in the normal controls. At 8 weeks of abstinence, ACTH/cortisol responses were significantly higher than 2 weeks previously, and were not distinguishable from the increments observed in the normal controls (76 and 68% higher than baseline, respectively, for ACTH and cortisol). CONCLUSIONS: In concurrence with previous reports showing alterations of the HPA axis in the central nervous system in alcohol-dependent subjects, these data show a defect of the neuroendocrine mechanism(s) underlying the ACTH/cortisol response to physical exercise for at least a month after alcohol withdrawal, with reconstitution of a normal hormonal response at 8 weeks.     

The combined dexamethasone-suppression/CRH-stimulation test in alcoholics during and after acute withdrawal

BACKGROUND: Chronic alcoholism is often accompanied by disturbances of the hypothalamic-pituitary-adrenal (HPA) system. Patients with alcoholism frequently show nonsuppression in the dexamethasone (Dex) suppression test and also a blunted increase of adrenocorticotropin (ACTH) after injection of corticotropin-releasing hormone (hCRH). However, the underlying mechanisms have not been fully elucidated. The combined Dex/CRH test (pretreatment with 1.5 mg dexamethasone at 2300 hr, injection of 100 microg hCRH at 1500 hr the next day) has been established as a more sensitive tool to investigate HPA system regulation in depressed patients. METHODS: We studied the effect of the combined Dex/CRH test in 19 alcoholic inpatients (9 male, 10 female) during and after withdrawal along with 19 healthy controls. RESULTS: Compared to normal controls, patients showed a severely dysregulated HPA system during withdrawal, with significantly elevated cortisol and ACTH response to hCRH after pretreatment with dexamethasone. After completed withdrawal, cortisol levels after injection of hCRH were almost normalized while ACTH values were partially lower in patients, compared to controls. CONCLUSIONS: We conclude that the HPA system is severely disturbed during alcohol withdrawal, possibly reflecting an exaggerated release of hypothalamic corticotropin and vasopressin.     

Alcohol and aldehyde dehydrogenase gene polymorphisms influence susceptibility to esophageal cancer in Japanese alcoholics

BACKGROUND: Studies have consistently demonstrated that inactive aldehyde dehydrogenase-2 (ALDH2), encoded by ALDH2*1/2*2, is closely associated with alcohol-related carcinogenesis. Recently, the contributions of alcohol dehydrogenase-2 (ADH2) polymorphism to alcoholism, esophageal cancer, and the flushing response have also been described. METHODS: To determine the effects of ALDH2 and ADH2 genotypes in genetically based cancer susceptibility, lymphocyte DNA samples from 668 Japanese alcoholic men more than 40 years of age (91 with and 577 without esophageal cancer) were genotyped and the results were expressed as odds ratios (ORs). This study also tested 82 of the alcoholics with esophageal cancer to determine whether cancer susceptibility is associated with patients' responses to simple questions about current or former flushing after drinking a glass of beer. RESULTS: The frequencies of ADH2*1/2*1 and ALDH2*1/2*2 were significantly higher in alcoholics with, than in those without, esophageal cancer (0.473 vs. 0.289 and 0.560 vs. 0.099, respectively). After adjustment for drinking and smoking, the analysis showed significantly increased cancer risk for alcoholics with either ADH2*1/2*I (OR = 2.03) or ALDH2*1/2*2 (OR = 12.76). For those having ADH2*1/2*1 combined with ALDH2*1/2*2, the esophageal cancer risk was enhanced in a multiplicative fashion (OR = 27.66). Responses to flushing questions showed that only 47.8% of the ALDH2*1/2*2 heterozygotes with ADH2*1/ 2*1, compared with 92.3% of those with ALDH2*1/2*2 and the ADH2*2 allele, reported current or former flushing. Genotyping showed that for alcoholics who reported ever flushing, the questionnaire was 71.4% correct in identifying ALDH2*1/2*2 and 87.9% correct in identifying ALDH2*1/2*1. CONCLUSION: Japanese alcoholics can be divided into cancer susceptibility groups on the basis of their combined ADH2 and ALDH2 genotypes. The flushing questionnaire can predict high risk ALDH2*1/2*2 fairly accurately in persons with ADH2*2 allele, but a reliable screening procedure for the highest risk gene combination (ADH2*1/2*1 and ALDH2*1/2*2) will require further investigation.     

Reduced EEG alpha power in the male and female offspring of alcoholics

Abnormalities in resting EEG may be associated with a predisposition to alcoholism. Research also suggests that high levels of negative affect are important mediators of the predisposition to alcoholism in the offspring of alcoholics. This study tested the hypothesis that the offspring of alcoholics show deficits in EEG alpha and excessive EEG beta activity, which, in turn, would be associated with high levels of negative affect. Participants were 37 men and 27 women with a positive family history of alcoholism and 37 men and 29 women with a negative family history of alcoholism. Personal and family history of psychopathology, psychological traits, and resting EEG were each assessed in separate testing sessions. Results indicated that subjects with a family history of alcoholism had reduced relative and absolute alpha power in occipital (O1, O2) and frontal (F3, F4, Fz) regions, and increased relative beta in both regions compared with subjects with a negative family history of alcoholism. EEG alpha and beta activity were not significantly correlated with trait anxiety, a diagnosis of depression, or antisocial traits. The results suggest that deficits in resting EEG alpha are associated with risk for alcoholism, although their etiological significance is unclear.     

Mismatch negativity and auditory sensory memory in chronic alcoholics

BACKGROUND & METHODS: Preattentive auditory processing and sensory memory were investigated by means of mismatch negativity (MMN) in a sample of 22 middle-aged abstinent chronic alcoholics and 25 age-matched healthy controls. Stimuli were presented at two inter-stimulus intervals (ISIs, 0.75 sec and 2.0 sec) in separate blocks. RESULTS: No significant differences in amplitude or latency of MMN were found between alcoholic and control subjects in either of the two ISI conditions. However, when age was included as a factor in the analysis, MMN amplitude was attenuated in chronic alcoholics who were older than 40 years of age. CONCLUSIONS: These results indicate that the automatic stimulus-change detector mechanism associated with MMN generation is impaired in chronic alcoholics over the age of 40, suggesting that the neurotoxic effects of chronic consumption of alcohol are more prone to appear after a critical age.     

Ritanserin in relapse prevention in abstinent alcoholics: results from a placebo-controlled double-blind international multicenter trial. Ritanserin in Alcoholism Work Group

Ritanserin, a long-acting specific 5-HT2 receptor antagonist, revealed promising effects on alcohol intake behavior in both animal and preliminary human studies. To test its effectiveness in alcohol dependence this phase III clinical trial was initiated. In a placebo-controlled, randomized, double-blind international multicenter study 493 patients with moderate or severe alcohol dependence (DSM-III-R) were treated with three doses of ritanserin 2.5 mg/day (n = 122), 5 mg/day (n = 123), 10 mg/day (n = 126), or placebo (n = 122) over a period of 6 months. Ritanserin was well tolerated. The most frequent adverse experiences were headache and insomnia. A small increase in weight in the ritanserin-treated patients was observed. There were no significant differences between any dose of ritanserin and placebo in the relapse-rate, the time to relapse, craving for alcohol, or quantity and frequency of drinking after relapse. So far, neither ritanserin nor any other serotonergic medication has shown its specific effectiveness in relapse prevention in alcohol dependence.     

Elevated myo-inositol in gray matter of recently detoxified but not long-term abstinent alcoholics: a preliminary MR spectroscopy study

BACKGROUND: Individuals in short-term abstinence from chronic alcohol consumption commonly have neuropsychological impairments with parallel abnormalities in brain structure. Stable, long-term sobriety often results in improvements in both brain structure and function, although the mechanisms underlying these changes are currently not well understood. METHODS: To investigate further the neurobiological underpinnings of alcohol-associated brain abnormalities in short-term and long-term abstinence from alcohol, proton magnetic resonance spectroscopy (echo time, 35 msec; repetition time, 1.5 sec) was used to assay metabolites in the anterior centrum semiovale, anterior cingulate gyrus, and right thalamus of two groups of non-Korsakoff alcoholic men, at different stages of abstinence, compared with a control group of alcohol-nonabusing men. Absolute concentrations of N-acetylaspartate, choline, myo-inositol, and creatine were measured in four recently detoxified alcoholics (mean age, 48.7 years; median abstinence, 41.5 days), five long-term abstinent alcoholics (mean age, 45.1 years; median abstinence, 1.7 years), and five nonalcoholic controls (mean age, 45.0 years). RESULTS: Although there were no between-group differences in concentrations of N-acetylaspartate, choline, or creatine, recently detoxified alcoholics had significantly higher myo-inositol in the thalamus, compared with controls and long-term abstinent alcoholics, and significantly higher myo-inositol in the anterior cingulate gyrus, compared with the controls. CONCLUSIONS: Elevations in myo-inositol in recently detoxified alcoholics are compatible with an acute alcohol cytotoxicity model. myo-Inositol is elevated in hyperosmolar states such as hypernatremia, renal failure, and diabetes; alcohol-induced hyperosmolarity may trigger accumulation of myo-inositol to stabilize the intracellular environment. Increases in myo-inositol may also reflect proliferation or activation of glia. The reduction of myo-inositol to control group levels in long-term abstinent alcoholics may reflect osmolar stability in abstinent alcoholics and/or a reduction in glial cell activation.     

Visual P3a in male alcoholics and controls

The goal of this study was to assess the P3a component of event-related potentials in a population of abstinent, chronic alcoholics. A three-stimulus visual oddball paradigm was used to elicit robust P3a components in a large group of well-characterized male alcoholics (n = 44) and controls (n = 28). The task required subjects to make a difficult perceptual discrimination between randomly presented, frequently occurring vertical lines (.80) and infrequent target lines that were tilted 2 degrees to the right of vertical (.10) by only responding with a button press to the target stimuli. A nontarget infrequent horizontal line occurred (.10) randomly to which no response was made. The target stimulus elicited robust late P3b components with a parietal maximum amplitude, and the nontarget stimulus elicited reliable P3a components with a fronto-central maximum amplitude distribution. Group differences in P3a were assessed using repeated measures ANCOVA analyses in five scalp regions. Alcoholic subjects produced smaller P3a amplitudes over the central, parietal, temporal, and occipital areas compared with controls. Current source density analyses supported these findings with extension of the differences between the groups to the frontal region. The results suggest that the P3a may be important in the evaluation of alcoholism and its heritability. Theoretical implications are discussed.