Blockade of cue-induced brain activation of abstinent alcoholics by a single administration of amisulpride as measured with fMRI

BACKGROUND: Once alcohol dependence is established, alcohol-associated cues may induce dopamine release in the reward system, which is accompanied by alcohol craving and may lead to relapse. In cocaine addicts, dopamine release in the thalamus was positively correlated with cocaine craving. We tested the effects of the atypical dopamine D(2/3) blocker amisulpride on cue-induced brain activation in a functional magnetic resonance imaging (fMRI) paradigm. METHODS: Alcohol-associated and neutral pictures were presented in a block design to 10 male abstinent alcoholics (1-3 weeks after detoxification) and 10 healthy men during fMRI. The fMRI scans were acquired before and 2 hours after the oral application of 400 mg amisulpride. Before and after each scan, alcohol craving was measured with visual analogue scales. RESULTS: Before the application of amisulpride, alcohol versus control cues elicited a higher blood oxygen level-dependent (BOLD) signal in the left frontal and orbitofrontal lobe, left cingulate gyrus, bilateral parietal lobe, and bilateral hippocampus in alcoholics compared with healthy controls. After amisulpride, alcoholics showed a reduced activation in the right thalamus compared with the first scan. Alcoholics no longer showed significant differences in their cue-elicited BOLD response after amisulpride medication compared with medication-free controls. Self-reported craving was not affected by amisulpride medication. CONCLUSIONS: Amisulpride medication was associated with reduced cue-induced activation of the thalamus, a brain region closely connected with frontostriatal circuits that regulate behavior and may influence relapse risk.     

Regional brain metabolism during alcohol intoxication

BACKGROUND: Ethanol has a broad range of actions on many neurotransmitter systems. The depressant actions of ethanol in the brain are related in part to facilitation of gamma-aminobutyric acid (GABA) neurotransmission via its interaction with the benzodiazepine/GABA receptor complex. The purpose of this study was to evaluate the effects of ethanol on regional brain metabolism in 10 healthy right-handed men. The results were compared with those we previously published in a different group of 16 normal male subjects who received intravenous lorazepam, a benzodiazepine drug that also enhances GABA neurotransmission. METHODS: The subjects were scanned with positron emission tomography and [F-18] fluorodeoxyglucose twice: 40 min after the end of placebo (diet soda) or ethanol (0.75 g/kg) oral administration. Image data sets were analyzed by using both the region of interest and the statistical parametric mapping (SPM) approach. SPM was used to generate a difference image between baseline and ethanol, which we compared to the difference image between baseline and lorazepam (30 microg/kg). RESULTS: Ethanol significantly increased self-reports of "high" (p < or = 0.0001), dizziness (p < or = 0.004), and intoxication (p < or = 0.0001). Ethanol significantly decreased whole brain (-25 +/- 6%, p < or = 0.0001) and regional metabolism. Normalization of the regional measures by whole brain metabolism (relative measures) showed that ethanol decreased relative metabolic activity in occipital cortex (-4.9 +/- 4.1%, p < or = 0.006), whereas it increased relative metabolic act in left temporal cortex (+3.5 +/- 2.9%, p < or = 0.006) and left basal ganglia (+9 +/- 6.3%, p < or = 0.0009). SPM analyses revealed the same pattern of responses as the relative measures, showing decreases in occipital cortex and increases in left temporal cortex. Comparison of the relative measures and the SPM analyses obtained with lorazepam data revealed a similar pattern of effects, with relative decreases in occipital cortex (-7.8 +/- 4.8%) and relative increases in left temporal cortex (+3.8 +/- 5.7%). Lorazepam, but not ethanol, also decreased thalamic metabolism (-11.2 +/- 7.2%). CONCLUSIONS: These results support similar though not identical mechanisms for the effects of alcohol and benzodiazepines on brain glucose metabolism. The fact that lorazepam, but not alcohol, reduced thalamic metabolism, an effect associated with sleepiness, could explain the higher sedative effects of lorazepam than of alcohol.     

Multiple Previous Alcohol Detoxifications Are Associated With Decreased Medial Temporal and Paralimbic Function in the Postwithdrawal Period

BACKGROUND: Functional neuroimaging studies after alcohol cessation have demonstrated that chronic alcohol use globally reduces neuronal activity for several weeks. Less is known about the effects of previous alcohol use patterns on regional brain activity. Multiple previous alcohol detoxifications are associated with a worse clinical course and increased risk of seizures, perhaps due to sensitization of key brain structures. We performed the following imaging study in alcoholics in the postwithdrawal period to determine if blood flow in medial temporal structures would differ as a function of previous alcohol use (i.e., whether regions were kindled or sensitized due to multiple detoxifications). METHODS: Fourteen adults meeting DSM-IV criteria for alcohol dependence (mean age 35, 8 SD; 10 men) and participating in a double-blind detoxification medication study underwent a brain perfusion Tc99 m-ECD (Neurolite) single photon emission computed tomography scan on days 7 through 9 (mean 7.6, .5 SD) after their last drink and 2 to 3 days since their last detoxification medication. Seven nonpsychiatrically ill, nonalcohol-dependent healthy adults were scanned as control subjects. RESULTS: Alcoholics compared with controls had widely reduced relative activity in cortical secondary association areas and relatively increased activity in the medial temporal lobes (p < 0.01). Five alcoholic patients with > or = 2 previous detoxifications were compared with five patients in their first detoxification (age and detoxification medication matched). Multiple detoxification patients had significantly lower relative activity in bilateral anterior temporal poles and medial temporal lobes and in visual cortex (p < 0.01) compared with first episode patients. CONCLUSIONS: These studies are consistent with other studies comparing alcoholics and controls. They also suggest that on day 7 of detoxification, alcoholic subjects with multiple previous detoxifications have decreased visual cortex, medial temporal lobes, and anterior paralimbic blood flow, compared with those in their first detoxification. Further studies seem warranted to confirm these initial exploratory results.     

Regional Cerebral Metabolism in Female Alcoholics of Moderate Severity Does Not Differ From That of Controls

It is generally believed that women are more vulnerable to alcohol's toxic effects than men. Studies in male alcoholics have consistently shown reductions in brain glucose metabolism. However, such studies have not been done in female alcoholics. The purpose of this study was to evaluate if similar or worse brain metabolic abnormalities occurred in female alcoholics. For this purpose, we measured regional brain metabolism with positron emission tomography and [¹⁸F]fluorodeoxyglucose in 10 recently detoxified female alcoholics and compared it with that in 12 age-matched female controls. There were no differences between alcoholics and control females in regional brain glucose metabolism whether we used regions of interest analysis or statistical parameter maps methods. These results do not support a higher toxicity for the effects of alcohol in the female brain, as assessed with regional brain glucose metabolism, because metabolic values in female alcoholics did not differ from those of controls, whereas metabolic values in male alcoholics are generally lower than those in controls. However, this study is confounded by the fact that the severity of alcohol use in these female alcoholics was less than that of the male alcoholics previously investigated in positron emission tomography studies. Future studies in male subjects with alcoholism of moderate severity are required to address gender differences in sensitivity to alcohol effects in brain metabolism.     

Effects of alcoholism and continued abstinence on brain volumes in both genders

Background: Alcohol abuse has detrimental effects on cerebral function, metabolism, and volume. Some of these effects were found to be at least partially reversible with continued abstinence. Furthermore, it has been reported that there are different effects of alcohol on brain volumes for women compared with men, but the results concerning the interaction between alcohol dependence and gender are inconsistent. With this study, we aimed to further investigate this question by examining the global gray matter (GM) and white matter (WM) changes as well as regional and local GM changes detected by voxel‐based morphometry (VBM) in male and female alcoholic patients a few weeks after detoxification and the corresponding changes in a subgroup of these patients 3 months later. Methods: A total of 50 patients, consecutively admitted for alcohol withdrawal treatment, participated in this study and were followed up for at least 3 months into abstinence. High‐resolution structural images were processed with SPM8 using an optimized VBM protocol. Results: Global cerebrospinal fluid (CSF) volume was increased and WM and GM volume decreased equally in male and female patients. A gender by diagnosis interaction was found neither for global nor for regional volumes or VBM data. VBM whole brain analysis yielded a significant GM volume loss in the patient group in the cingulate gyrus and the insula in both hemispheres. Region of interest analysis for the initial and 3 months follow‐up scans yielded significant gains in regional volumes, particularly the cingulate gyrus and the insula in the group of abstinent patients, whereas no volume change at all is found in the patients who had relapsed. Conclusions: Our study confirms widespread cerebral volume loss in recently detoxified alcoholics. The effects of alcohol dependence seem to have equally adverse effects on brain morphometry in males and females.     

Altered Motor Cortex Excitability to Magnetic Stimulation in Alcohol Withdrawal Syndrome

Background: Alcohol addiction is a complex brain disease caused by alterations in crucial neurotransmitter systems, including gamma‐aminobutyric acid (GABA) and glutamate. These disturbances could be revealed by changes in cortical excitability parameters, as assessed by transcranial magnetic stimulation (TMS). This study was aimed to further investigate the complex pathophysiology of alcohol withdrawal syndrome (AWS). Methods: Motor cortex excitability was examined in 13 subjects with AWS in a mild predelirial state, in 12 chronic alcoholics and in 15 age‐matched control subjects, using a range of TMS protocols. Central motor conduction time, resting and active motor threshold, duration of the cortical silent period, short latency intracortical inhibition (SICI), and intracortical facilitation (ICF) to paired TMS were examined. Results: Intracortical facilitation was significantly increased in the AWS patients when compared with the chronic alcoholics and the control subjects. The other TMS parameters did not differ significantly from the controls. Administration of a single oral dose of the glutamatergic antagonist riluzole in a subgroup of 8 patients significantly reduced ICF; motor threshold and SICI were not affected by riluzole. Conclusion: Transcranial magnetic stimulation shows a selective increase in intracortical facilitation after ethanol withdrawal. Our findings support the theory that altered glutamatergic receptor function plays an important role in the pathogenesis of human alcohol withdrawal. This study provides further physiological evidence that antiglutamatergic approaches represent an efficacious alternative for treating alcohol withdrawal symptoms.     

Reduced fronto-cerebellar functional connectivity in chronic alcoholic patients

Background: Alcohol dependence is associated with neurocognitive deficits related to neuropathological changes in structure, metabolism, and function of the brain. Impairments of motor functioning in alcoholics have been attributed to well‐characterized neuropathological brain abnormalities in cerebellum. Methods: Using functional magnetic resonance imaging (fMRI), we studied in vivo the functional connectivity between cerebellar and cortical brain regions. Participants were 10 uncomplicated chronic alcoholic patients studied after 5 to 7 days of abstinence when signs of withdrawal had abated and 10 matched healthy controls. We focused on regions of prefrontal, frontal, temporal, and parietal cortex that exhibited an fMRI response associated with nondominant hand finger tapping in the patients but not in the controls. We predicted that fronto‐cerebellar functional connectivity would be diminished in alcoholics compared with controls. Results: Functional connectivity in a circuit involving premotor areas (Brodmann Area 6) and Lobule VI of the superior cerebellum was reduced in the patients compared with the controls. Functional connectivity was also reduced in a circuit involving prefrontal cortex (Brodmann Area 9) and Lobule VIII of the inferior cerebellum. Reductions in connectivity were specific to fronto‐cerebellar circuits and were not found in other regions examined. Conclusions: Our findings show a pattern in recently abstinent alcoholic patients of specific deficits in functional connectivity and recruitment of additional brain regions for the performance of a simple finger‐tapping task. A small sample, differences in smoking, and a brief abstinence period preclude definitive conclusions, but this pattern of diminished fronto‐cerebellar functional connectivity is highly compatible with the characteristic neuropathological lesions documented in alcoholics and may reflect brain dysfunction associated with alcoholism.     

Effect of alcohol withdrawal on liver transaminase levels and markers of liver fibrosis

BACKGROUND AND AIM: Acute alcohol withdrawal causes changes in hepatic blood flow and metabolism that may result in liver damage. This study aims to assess liver function tests and markers of hepatic fibrogenesis following alcohol withdrawal in alcoholics with clinically compensated liver disease. METHODS: Serial liver function tests and clinical assessments were performed on 22 male alcoholics during alcohol withdrawal. Plasma tissue inhibitor of metalloproteinase 1 (TIMP1), an inhibitor of collagen degradation, and plasma amino-terminal procollagen III peptide (PIIINP), a collagen precursor molecule, were measured in these alcoholics and in 11 control subjects. RESULTS: Transaminase levels did not change significantly over 7 days when all subjects were analyzed together. However, 32% of subjects showed a marked transaminase rise. These subjects did not differ from the others in baseline characteristics or short-term outcome, but had a greater benzodiazepine requirement. Only one subject consumed paracetamol (acetaminophen; 1-2 g/day). He had the largest transaminase rise. By comparing PIIINP assays, intact PIIINP concentration appears to increase following alcohol withdrawal. The TIMP1 levels were elevated in alcoholic subjects, but did not change following withdrawal. CONCLUSIONS: Increasing PIIINP suggests that hepatic fibrogenesis increases, or hepatic clearance falls, during acute alcohol withdrawal. The TIMP1 elevation in these alcoholics suggests that the inhibition of collagen degradation occurs while liver disease is still compensated. The period following alcohol withdrawal may be a time of marked increased susceptibility to paracetamol. The biochemical changes we observed were not associated with adverse short-term outcome, but the cumulative effect after repeated episodes of abrupt withdrawal may be of concern.     

Disruptions in sleep time and sleep architecture in a mouse model of repeated ethanol withdrawal

BACKGROUND: Insomnia and other sleep difficulties are perhaps the most common and enduring symptoms reported by alcoholics undergoing detoxification, especially those alcoholics with a history of multiple detoxifications. While some studies have reported sleep disruptions in animal models after chronic ethanol exposure, the reports are inconsistent and few address sleep architecture across repeated ethanol exposures and withdrawals. The present study evaluated sleep time and architecture in a well-characterized mouse model of repeated chronic ethanol exposure and withdrawal. METHODS: C57BL6/J mice were fitted with electrodes in frontal cortex, hippocampus, and nuchal muscle for collection of continuous electroencephalogram (EEG)/electromyogram (EMG) data. Baseline data were collected, after which mice received 4 cycles of 16-hour exposure to alcohol (ethanol: EtOH) vapor separated by 8-hour periods of withdrawal or similar handling in the absence of EtOH vapor. Ethanol-exposed mice attained a blood ethanol concentration of 165 mg%. Upon completion of vapor exposure, EEG/EMG data were again collected across 4 days of acute withdrawal. Data were subjected to automated analyses classifying 10-second epochs into wake, non-rapid eye movement (REM) sleep, or REM sleep states. RESULTS: Mice in withdrawal after chronic EtOH exposure showed profound disruptions in the total time asleep, across the acute withdrawal period. Sleep architecture, the composition of sleep, was also disrupted with a reduction in non-REM sleep concomitant with a profound increase in REM sleep. While altered sleep time and non-REM sleep loss resolved by the fourth day of withdrawal, the increase in REM sleep ("REM rebound") persisted. CONCLUSIONS: These results mirror those reported for the human alcoholic and demonstrate that EtOH withdrawal-induced sleep disruptions are evident in this mouse model of alcohol withdrawal-induced sensitization. This mouse model may provide mechanisms to investigate fully the high correlation between unremitting sleep problems and increased risk of relapse documented clinically.     

Effects of the glucocorticoid antagonist, mifepristone, on the consequences of withdrawal from long term alcohol consumption

Background: Studies were carried out to test the hypothesis that administration of a glucocorticoid Type II receptor antagonist, mifepristone (RU38486), just prior to withdrawal from chronic alcohol treatment, would prevent the consequences of the alcohol consumption and withdrawal in mice. Materials and Methods: The effects of administration of a single intraperitoneal dose of mifepristone were examined on alcohol withdrawal hyperexcitability. Memory deficits during the abstinence phase were measured using repeat exposure to the elevated plus maze, the object recognition test, and the odor habituation/discrimination test. Neurotoxicity in the hippocampus and prefrontal cortex was examined using NeuN staining. Results: Mifepristone reduced, though did not prevent, the behavioral hyperexcitability seen in TO strain mice during the acute phase of alcohol withdrawal (4 hours to 8 hours after cessation of alcohol consumption) following chronic alcohol treatment via liquid diet. There were no alterations in anxiety‐related behavior in these mice at 1 week into withdrawal, as measured using the elevated plus maze. However, changes in behavior during a second exposure to the elevated plus maze 1 week later were significantly reduced by the administration of mifepristone prior to withdrawal, indicating a reduction in the memory deficits caused by the chronic alcohol treatment and withdrawal. The object recognition test and the odor habituation and discrimination test were then used to measure memory deficits in more detail, at between 1 and 2 weeks after alcohol withdrawal in C57/BL10 strain mice given alcohol chronically via the drinking fluid. A single dose of mifepristone given at the time of alcohol withdrawal significantly reduced the memory deficits in both tests. NeuN staining showed no evidence of neuronal loss in either prefrontal cortex or hippocampus after withdrawal from chronic alcohol treatment. Conclusions: The results suggest mifepristone may be of value in the treatment of alcoholics to reduce their cognitive deficits.     

Sodium sensitivity as a main determinant of blood pressure changes during early withdrawal in heavy alcoholics

BACKGROUND: Stimulated sympathetic nervous system, renin-angiotensin-aldosterone system, vasopressin, and cortisol are thought to affect blood pressure in early withdrawal of alcoholics. Hyperactivity of sodium-retaining systems with consequent volume expansion also could interact with sodium sensitivity as previously found in long-term withdrawing alcoholics. METHODS: To investigate this hypothesis, blood pressure and sodium balance were measured during the first 8 days of withdrawal in 18 chronic alcoholics on a 150 mM Na diet. Results were related to the Salt Sensitivity Index of blood pressure as measured in the same alcoholics after 1 year of abstinence. RESULTS: Early withdrawal study: there was a positive sodium balance (+288.6 +/- 45.6 mM; p < 0.0001) and rise in mean arterial pressure (+11.8 +/- 2.9 mm Hg; p = 0.001) during early withdrawal on 150 mM Na diet. Salt Sensitivity Study after long-term detoxification: the shift from low (55 mM) to high sodium (260 mM) intake produced a larger (p = 0.04) increase in mean arterial pressure in alcoholics (+9.3 +/- 2.0 mm Hg) than in 30 teetotal controls (+5.1 +/- 1.1) (Salt Sensitivity Index, 0.047 +/- 0.008 vs. 0.023 +/- 0.0053; p < 0.05). Changes in mean blood pressure during withdrawal were highly related to sodium sensitivity index (r = 0.8; p < 0.001). CONCLUSIONS: Early withdrawing alcoholics exposed to a normal sodium intake experience positive Na balance and increase in blood pressure that is related to sodium sensitivity measured after long-term detoxification. This suggests that salt sensitivity plays a key role in blood pressure regulation in early withdrawing alcoholics.     

Effects of lorazepam treatment for multiple ethanol withdrawals in mice

Background: Although many alcohol‐dependent patients present with a history of prior detoxifications, the efficacy and safety of pharmacotherapy in the context of multiple ethanol withdrawal experiences have not been extensively studied. The purpose of this study was to evaluate the ability of lorazepam treatment for multiple withdrawals to prevent or blunt the development/expression of sensitized central nervous system hyperexcitability during a subsequent untreated withdrawal episode. A mouse model of withdrawal sensitization involving repeated ethanol withdrawals was used. Methods: Adult male C3H/He mice were exposed to different patterns of chronic ethanol vapor in inhalation chambers. One group received four cycles of 16 hr of ethanol exposure separated by 8‐hr withdrawal periods, another group was tested after a single 16‐hr exposure period, and a final group served as ethanol‐naïve controls. These groups were further divided into lorazepam dosage (0.25–1.0 mg/kg) conditions. Lorazepam was administered 1 hr into each of the first three withdrawal cycles (or equivalent times); no drug injections were given during the final (fourth) withdrawal cycle. The ability of lorazepam treatment to alter development and expression of sensitized handling‐induced convulsions (HIC), as well as changes in pentylenetetrazol seizure threshold dosage during an untreated withdrawal episode, was examined. Separate animals were used to assess the effects of lorazepam treatment on blood ethanol clearance and plasma levels of the benzodiazepine during the test withdrawal cycle. Results: Lorazepam dose‐dependently reduced HIC activity during successive withdrawal cycles, and this resulted in attenuated expression of the sensitized HIC response during the acute phase of a subsequent untreated withdrawal episode. However, HIC activity was exacerbated at later time points during this final test withdrawal in mice that had received lorazepam treatment for earlier withdrawals. A similar pattern of results was obtained for changes in pentylenetetrazol seizure threshold dosage. These results do not seem to be due to pharmacokinetic factors, because peak blood ethanol levels, rate of ethanol elimination, and plasma levels of lorazepam did not significantly differ among groups during the final test withdrawal cycle. Conclusions: Blocking central nervous system hyperexcitability during repeated ethanol withdrawals with lorazepam effectively blunts the development and expression of sensitized seizure activity during the acute phase of a subsequent unmedicated withdrawal episode. At later time points, withdrawal‐related seizure activity was exacerbated, and this is possibly reflective of an interaction between protracted ethanol withdrawal and withdrawal from the benzodiazepine. The clinical implications of these findings suggest that repeated use of benzodiazepines for treatment of multiple ethanol withdrawals may have some initial beneficial effects, but such treatment may also place patients at increased risk of seizures at later time points.     

Bone mineral density and abstention-induced changes in bone and mineral metabolism in noncirrhotic male alcoholics.

BACKGROUND AND PURPOSE: Abuse of alcohol may derange bone metabolism and cause osteoporosis. Due to confounding factors associated with alcohol abuse, however, the effect of alcohol itself on bone loss remains obscure. The influence of alcohol intake on bone and mineral metabolism is rather well known, but how the metabolism normalizes during withdrawal has rarely been investigated. The aims of the present study were to evaluate the alcohol-induced changes of bone and mineral metabolism and their recovery during abstention, and to reassess any possible link between alcohol abuse and osteoporosis. PATIENTS AND METHODS: We studied 27 non-cirrhotic male alcoholics hospitalized for 2 weeks for withdrawal. For comparison, three groups of control subjects were examined. Serum and urinary parameters of bone and mineral metabolism as well as intestinal absorption of calcium were determined at the beginning and end of the treatment period. Bone mineral density (BMD) was measured by dual-energy x-ray absorptiometry at four axial sites (lumbar spine, femoral neck, Ward's triangle, trochanter). RESULTS: On admission, bone formation in the alcoholics was reduced as reflected by decreased serum levels of osteocalcin (-28%; p < 0.05) and procollagen I carboxyterminal propeptide (-17%; p < 0.05). Both parameters normalized within 2 weeks of abstention (p < 0.0001 and p < 0.01, respectively). Urinary hydroxyproline, a parameter of bone resorption, was at the control level on admission and increased slightly during abstention (p < 0.05). Serum ionized calcium increased by 3% (p < 0.0001) during withdrawal. Concomitantly, serum free fatty acids (FFA) decreased by 38% (p < 0.001), and there existed an inverse correlation (r = -0.50, p < 0.05) between changes in ionized calcium and FFA. Serum levels of intact parathyroid hormone and vitamin D metabolites were similar in patients and controls throughout the whole observation period. Intestinal absorption of calcium measured by stable strontium was 37% higher in alcoholics than in controls (p < 0.001); it decreased to nearly normal toward the end of the treatment period. Mean axial BMD did not differ between patients and controls at any of the four measurement sites. However, BMD decreased parallel with duration of drinking history in the alcoholics at all axial sites (p < 0.05 to < 0.01, analysis of covariance with age and weight as covariates). CONCLUSIONS: Decreased bone formation, which is uncoupled from ongoing bone resorption, recovers completely during 2 weeks of abstention. In the absence of confounding factors, the central BMD is normal in noncirrhotic male alcoholics, although the negative effect of alcohol on BMD is evident when duration of excessive drinking is taken into account.     

Glucose tolerance in chronic alcoholics after alcohol withdrawal: effect of accompanying diet

The effect of alcoholism or acute alcohol ingestion on carbohydrate metabolism is not clear. The metabolic features of alcoholics cannot be easily achieved in normal men submitted to investigations concerning the effects of alcohol on glucose tolerance. Undernutrition and/or malnutrition characterize the eating behavior of alcoholics. It is also well-known that diet is an important determinant of carbohydrate tolerance. Thus, we studied the effects of a controlled diet on glucose tolerance and insulin release in a group of chronic alcoholics, with or without withdrawal from alcohol. Twenty-two subjects took part in the study; their mean caloric intake was 2,805 +/- 91 kcal/d, 58% of which was due to alcohol. In all subjects five days after an isocaloric diet and no alcohol, we performed an oral glucose tolerance test (OGTT). After that, the subjects were divided into three subgroups: group A, eight subjects with alcohol withdrawal and an 17.5 kcal/kg/d diet; group B, eight subjects with alcohol withdrawal and a 35 kcal/kg/d diet, and group C, six subjects with a 35 kcal/kg/d diet plus ethanol 200 g/d. After 3 weeks a second OGTT was performed. We found a significant improvement of the glucose tolerance and of the release of insulin in group B as well as group C; the alcohol withdrawal per se was irrelevant to the observed modifications of the glucose tolerance. Our data suggest that a poor diet would be a major cause of carbohydrate intolerance in alcoholics.     

Blunted rostral anterior cingulate response during a simplified decoding task of negative emotional facial expressions in alcoholic patients

BACKGROUND: Alcoholism is characterized by deficits in emotional functioning as well as by deficits in cognitive functioning. However, most brain imaging research on alcoholism has focused on cognition rather than emotion. METHOD: We used an event-related functional magnetic imaging approach to examine alcoholics' brain blood oxygenation level dependent (BOLD) response to evaluation of emotional stimuli and to compare their response to that of nonalcoholic controls. The task used was a simplified variant of a facial emotion-decoding task in which subjects determined the intensity level of a target emotion displayed as a facial expression. Facial expressions of happy, sad, anger, disgust, and fear were used as stimuli. RESULTS: Alcoholics and controls did not differ in accurately identifying the intensity level on the simple emotional decoding task but there were significant differences in their BOLD response during evaluation of facial emotion. In general, alcoholics showed less brain activation than nonalcoholic controls. The greatest differences in activation were during decoding of facial expressions of fear and disgust during which alcoholics had significantly less activation than controls in the affective division of the anterior cingulate cortex (ACC). Alcoholics also had significantly less activation than controls in the affective division of the ACC, while viewing sad faces. Only to facial expressions of anger did the alcoholics show significant activation in the affective ACC and in this case, their BOLD response did not significantly differ from that of the controls. CONCLUSION: Alcoholics show a deficit in the function of the affective division of the ACC during evaluation of negative facial emotions that can serve as cues for flight or avoidance. This deficit may underlie some of the behavioral dysfunction in alcoholism.     

MRI Study of Brain Changes with Short-Term Abstinence from Alcohol

Magnetic resonance brain scans were obtained from 10 chronic alcoholics within 2 weeks of alcohol withdrawal, and 19 to 28 days later. Age-matched control subjects were scanned at comparable intervals. At the initial scan, the alcoholics had larger lateral ventricles than the controls; at the second scan, their ventricles were significantly smaller than at the first scan. Among the controls, there was no mean change in the size of the lateral ventricles between the first and second scan. This study demonstrates reversibility in ventricular enlargement with short-term abstinence from alcohol. The role of rehydration in this process and the possibility of further changes with continued abstinence remain to be tested.     

Ethanol-induced regulation of GABA-A subunit mRNAs in prefrontal fields of cynomolgus monkeys

BACKGROUND: Recent evidence indicates that functional impairment of the orbital and medial fields of the prefrontal cortex may underlie the deficits in executive control of behavior that characterize addictive disorders, including alcohol addiction. Moreover, previous studies have indicated that alcohol alters GABA neurotransmission and one substrate of these effects may be through the reconfiguration of the subunits constituting the GABA(A) receptor complex. Given that GABAergic transmission has an integral role in cortical processing, influencing local and interregional communication, understanding alcohol-induced alterations in GABA(A) receptors in prefrontal fields of the primate brain may provide insight into the functional impairment of these brain regions in the alcohol-addicted state and extend our understanding of the molecular consequences of long-term use in these critical brain regions. METHODS AND RESULTS: To address this problem, the effects of chronic ethanol self-administration in male cynomolgus monkeys on GABA(A) receptor subunit mRNA expression was studied in 3 frontal cortical fields: orbitofrontal cortex (OFC; area 13), anterior cingulate cortex (ACC; area 24), and the dorsolateral prefrontal cortex (DLPFC; area 46). Quantitative polymerase chain reaction revealed significant alterations in GABA(A) subunit mRNA expression in the OFC and DLPFC but not in the ACC. Specifically, expression of the alpha2, alpha4, beta1, beta3, and gamma1 to gamma3 subunit mRNAs was significantly less in the OFC, whereas the expression of beta1, beta2, gamma1, and delta subunit mRNAs was less in the DLPFC of alcohol-treated monkeys. CONCLUSION: These findings suggest that ethanol-induced alterations in GABA(A) function may be due to alterations in GABA(A) subunit mRNA levels and subunit-specific alterations are selective to particular cortical fields.     

Glutamate Receptors in the Frontal Cortex of Alcoholics

This study tests the hypothesis that glutamate receptors are altered in the brains of alcoholics as a result of chronic alcohol neurotoxicity. Release of the neurotransmitter glutamate after seizures or brain ischemia may damage postsynaptic neurons by increasing calcium flux through N-methyl-D-aspartate (NMDA) receptor-gated ion channels. Alcohol has two opposite effects on glutamate receptor ion channel complexes, depending upon the duration of exposure. Acute exposure to alcohol inhibits ion flow through these receptor- channel complexes, whereas chronic exposure up-regulates the number of these receptors and thereby increases ion flow. Acute withdrawal from alcohol results in hyperexcitability and seizures in the presence of up-regulated channels, thereby making postsynaptic neurons vulnerable to excitotoxic damage. We selected 13 histologically normal brains from alcoholics and 13 brains from controls from our brain bank that were matched for age, postmortem interval, and storage time. Maximal binding and affinities of glutamate receptor subtypes were determined by quantitative autoradiography in the superior frontal cortex, Brodmann area 8. The most alcohol-sensitive subtype, NMDA receptor-channel complexes, were modestly but consistently increased in alcoholics. This included agonist sites (NMDA-sensitive [³H]glutamate), and antagonist site [³H]CGP-39653), and a [³H]MK-801 binding site in the channel interior, although the increase of the latter did not reach statistical significance. Age, autopsy delay, time in storage, liver diseases, thiamine deficiency, CNS medications, and various diseases causing acute and chronic hypoxia did not significantly affect receptor density or affinity. In contrast, the other two glutamate channel subtypes, AMPA and kainate receptors, were not significantly different in alcoholics compared with controls. In conclusion, chronic alcoholism moderately increases the density of the NMDA subtype of glutamate receptors in the frontal cortex. This up-regulation may represent a stage of alcohol-induced chronic neurotoxicity.     

An in vivo study of the relationship between craving and reaction time during alcohol detoxification using the ecological momentary assessment

BACKGROUND: To study cognitive interference associated with craving for alcohol, the Ecological Momentary Assessment (EMA) method was used to measure the relationship between craving and reaction time. A secondary aim was the study of the predictive factors for craving during alcohol detoxification. The EMA enables both repeated measures of craving in a natural setting and the recording of reaction time without the patient being aware of this. METHODS: Craving for alcohol, reaction time, sadness and anxiety were recorded 8 to 12 times a day, over three weeks of detoxification in 14 alcoholics (n=1767 measures), on an electronic diary issuing random prompts. Mixed models were used for statistical analysis (alpha=5%, 1-beta=88%). RESULTS: Reaction time was significantly increased in univariate analysis when a craving episode occurred but this difference did not persist after multivariate analysis. Craving episodes were more frequent and intense than previously reported. Predictive factors of craving during detoxification were: age, gender, sadness, anxiety and the number of previous detoxifications. Antidepressants, anti-craving medications but not benzodiazepines were negatively associated to craving.     

Glutamate receptors in the cingulate cortex, hippocampus, and cerebellar vermis of alcoholics

This study tests the hypothesis that glutamate receptors are altered in the brains of alcoholics as a result of chronic alcohol neurotoxicity. Excessive release of the excitatory neurotransmitter glutamate may damage postsynaptic neurons by increasing calcium flux through N-methyl-D-aspartate (NMDA) receptor-gated ion channels. Alcohol has opposite effects on the NMDA receptor, depending on the duration of exposure. Acute exposure to alcohol inhibits ion flow through NMDA receptors, whereas chronic exposure upregulates the number of these receptors and thereby increases ion flow. Acute withdrawal from alcohol results in hyperexcitability and seizures in the presence of upregulated NMDA receptors, making postsynaptic neurons vulnerable to excitotoxic damage. For this study, 13 grossly and histologically normal brains from alcoholics and 13 brains from nonalcoholic controls were selected from our brain bank. The two groups were matched for age, postmortem interval, and storage time. Maximal binding and affinities of NMDA receptors were determined by quantitative autoradiography in the cingulate cortex, the cornu Ammonis of the hippocampus, and in the cerebellar vermis. Binding was determined with an agonist, L-[3H]glutamate, with a competitive antagonist, [3H]CGP-39653, and with an antagonist binding in the channel interior, [3H]MK-801. No significant differences were found in receptor densities or affinities between alcoholics and controls. Real differences were not likely to be obscured by nonalcohol-related variables because the groups were closely matched for age, autopsy delay, time in storage, and central nervous system medications. Various diseases causing acute and chronic hypoxia did not significantly affect receptor density or affinity. Liver diseases and thiamine deficiency were excluded. A long-lasting upregulation of the number or affinity of NMDA receptors is not a key feature of chronic alcoholics.