Chronic benzodiazepine usage and withdrawal in insomnia patients

We studied the sleep of patients with insomnia during continuous and very long-term use of benzodiazepines (BZDs), and after withdrawal. A group of 25 patients (mean age 44.3+/-11.8 years) with persistent insomnia, who had been taking BZDs nightly for 6.8+/-5.4 years was selected. The control group was comprised of 18 age-matched healthy individuals. Sleep stage parameters were analyzed during Night 1 (while taking BZDs), Night 2 (first night after completing BZD withdrawal), and Night 3 (15 days after gradual BZD withdrawal). Sleep data for control subjects was monitored in parallel. Sleep EEGs of the patients were analyzed using Period Amplitude Analysis (PAA), during Nights 1 and 3 only. During BZD use, a significant reduction of Total Sleep Time (TST) and increased sleep latency were found in the insomniac group when compared to controls. We found an increase in stage 2 non-REM (NREM) sleep, and a reduction in Slow Wave Sleep (SWS) when comparing to night 3 (after withdrawal). Sleep EEGs analysis showed an increase in sigma band and decrease in delta count in stages 2, 3, 4 NREM and REM sleep in the BZD group when comparing to night 3 (after withdrawal). During the BZD withdrawal period, six out of nine subjects taking lorazepam failed withdrawal. In the remaining 19 subjects, gradual withdrawal of BZDs was associated with immediate worsening of nocturnal sleep, as indicated by sleep parameters. However, 15 days after withdrawal (Night 3), some of the sleep structure parameters of patients were not significantly different from baseline (while taking BZDs), except for a significant increase in SWS and in delta count throughout most sleep stages, and a decrease in stage 2 NREM sleep. These values were not different from those shown by control subjects. REM sleep parameters showed no significant variation across the experimental conditions. Subjective sleep quality was significantly improved on Night 3 compared with Night 1. Conclusions: Chronic intake of BZDs may be associated with poor sleep in this population. A progressive 15-day withdrawal did not avoid an immediate worsening of sleep parameters. But at the end of the protocol, SWS, delta count, and sleep quality were improved compared to those recorded during the chronic BZD intake, despite the lack of change in sleep efficiency.     

Concurrent cocaine withdrawal is associated with reduced severity of alcohol withdrawal

The purpose of this study was to implement an empirical assessment of the clinical response to standard alcohol detoxification during withdrawal from both alcohol and cocaine. One hundred forty-nine males consecutively admitted in acute alcohol withdrawal to a hospital-based detoxification unit were studied. All subjects completed a 4-day chlordiazepoxide detoxification. Patients who used drugs other than cocaine were excluded. Fifty-five subjects withdrawing only from alcohol and 94 subjects withdrawing from both alcohol and cocaine, as evidenced by positive urinalysis and history, were studied. Both groups reported similar amounts of daily alcohol intake and had a similar age of onset of alcohol dependence. Parental alcoholism was equally frequent in both groups. Statistically, several variables were directly related to severity of alcohol withdrawal, including associated cocaine abuse, age, abnormal laboratory values, and duration of homelessness. As measured by the Alcohol Withdrawal Scale (AWS), alcohol withdrawal was less severe among cocaine users, not only at intake but throughout the 4-day detoxification. Singly addicted alcoholics were older and had longer drinking histories, more prior detoxifications, and more abnormal laboratory values than cocaine users. A multiple regression analysis demonstrated a significant relationship between cocaine and severity of alcohol withdrawal. Cocaine users more frequently requested reductions in chlordiazepoxide dosages than singly addicted alcoholics, complaining of dysphoria, sedation, and weakness. The severity of alcohol withdrawal was associated with recent cocaine use, age, laboratory abnormalities, and duration of homelessness. Concurrent cocaine withdrawal in the sample was associated with reduced severity of alcohol withdrawal. Possible neurobiological mechanisms, as well as study limitations affecting interpretation of the findings, are discussed. Tailored detoxification as opposed to standard detoxification regimens may be more appropriate for the clinical management of combined alcohol-cocaine withdrawal.     

Polysomnography during withdrawal with clomethiazole or placebo in alcohol dependent patients--a double-blind and randomized study

INTRODUCTION: The present study was designed to assess if the routine application of clomethiazole to ameliorate withdrawal symptoms in chronic alcohol dependent patients perpetuates sleep disturbances. METHODS: Twenty inpatients with alcohol dependence according to DSM-IV criteria received clomethiazole or placebo in a double-blind, randomized design upon admission. 11 patients were randomized to the clomethiazole group and 9 patients to the placebo group. During the first 5 days of treatment the patients received either clomethiazole (1st day: 3 x 384 mg, 2nd day: 4 x 384 mg, 3rd day: 3 x 384 mg, 4th day: 2 x 384 mg and 5th day: 1 x 384 mg) or placebo capsules at constant intervals. The patients spent two consecutive nights in the sleep laboratory at each of three assessment times: the first time at the beginning of abstinence (night 1 and 2, T0), the second time 6 days later (i. e. after 5 days of treatment and one day of discontinuation of clomethiazole or placebo: nights 6 and 7, T1) and the third time after 13 days (nights 13 and 14, T2). The first night at each of the three assessment times was an adaptation night. RESULTS: During the first two weeks of abstinence, the analysis of variance demonstrated a significant variation of Rapid Eye Movement (REM) sleep variables in the clomethiazole group. The placebo group showed no such variation. Clomethiazole evidently had a pronounced REM sleep suppressing effect, whereas the discontinuation of clomethiazole led to a REM sleep rebound. Furthermore, analysis of sleep continuity and sleep architecture variables showed that the clomethiazole group had significantly disturbed sleep at T1 in comparison to the placebo group. Simultaneous statistical testing with alcohol intake as covariate reduced the test power so that contrasts between the groups became nonsignificant. CONCLUSIONS: The REM sleep results are in line with earlier findings that REM sleep disinhibition in primary alcohol dependency is partly due to a REM sleep rebound after withdrawal from medication. Differences in the polysomnographic variables of sleep continuitiy and sleep architecture at T0 and T1 found between the clomethiazole and the placebo patients correspond to rebound insomnia following discontinuation of clomethiazole. Our findings indicate that drugs enforcing GABAergic neurotransmission may perpetuate the neuroadaptative effects caused by chronic alcohol consumption.     

Polysomnographic comparison between patients with primary alcohol dependency during subacute withdrawal and patients with a major depression

Complex neurobiological models based on animal research have been formulated in an attempt to explain the cyclic pattern of nonREM and REM sleep. The "reciprocal interaction model" of nonREM and REM sleep regulation, which has been updated to incorporate new evidence is still the most convincing. Therefore it is reasonable to apply this model also to REM sleep abnormalities such as shortened REM latency and increased REM density, observed in patients with depression and alcohol dependency. In a retrospective analysis baseline data from 40 subjects with primary alcohol dependency are compared with a group of 40 patients diagnosed with major depression (diagnoses according to DSM-III-R) and healthy subjects. All alcohol dependent patients were examined in the sleep laboratory during subacute withdrawal at least 7 days off medication and after at least 14 days of abstinence. The patients with major depression (at least 7 days off psychoactive medication) and the healthy subjects had been examined previously by polysomnography during the last few years in the context of various studies and were assembled from our database to match the group of alcohol dependent patients with respect to age and sex.Alcohol dependent patients exhibited similar disturbances in sleep continuity and REM sleep as depressed patients in comparison to healthy controls while parameters of sleep architecture were even more strongly disturbed in alcohol dependence.While enhanced sensitivity of cholinergic receptors is the most likely explanation for the increase in "REM pressure" in depressives, this appears not to apply to alcoholics, who rather exhibit a decreased response to cholinergic stimulation. Thus, according to the reciprocal interaction model of nonREM- and REM sleep regulation and in contrast to the interpretation of the findings in depressed patients, an impaired aminergic rather than an increased cholinergic neurotransmission might be responsible for the increased REM sleep pressure in alcohol dependent patients. Alternatively or in addition the REM anomalies in alcoholic patients could also be due to adaptive regulatory processes during chronic alcohol consumption that lead to downregulation of GABA(A)- and upregulation of NMDA-receptors or their intracellular signalling and become apparent with alcohol withdrawal. Such adaptive counterregulation might also explain the alterations in slow wave sleep found in alcoholics that are even more pronounced in these patients than in patients with major depression.     

Sleep and the cholinergic rapid eye movement sleep induction test in patients with primary alcohol dependence.

BACKGROUND: The present study investigated polysomnographically assessed sleep parameters in alcohol-dependent patients after withdrawal and in healthy control subjects during baseline and after a cholinergic stimulation paradigm. The aim of the study was to test whether sleep parameters, especially rapid eye movement (REM) sleep variables, may serve as predictors for relapse in alcohol-dependent patients. METHODS: Forty patients diagnosed with alcohol dependence were admitted to a specialized ward for alcohol withdrawal and were investigated by polysomnography at three time points: 2-3 weeks after withdrawal (T0) and at follow-up investigations 6 (T1) and 12 (T2) months after discharge from the hospital. A subgroup of patients (n = 17) was studied at T0 after challenge with galanthamine, a reversible cholinesterase inhibitor (cholinergic REM induction test, CRIT). Patients were compared with two control groups: a) 30 healthy control subjects (matched for age- and gender-distribution) for comparison at baseline conditions; and b) 17 age- and gender-matched control subjects for comparison with the CRIT. RESULTS: At baseline the patients showed significant disturbances of sleep continuity and sleep architecture (decreased slow-wave sleep, SWS) and exhibited an increase of "REM sleep pressure" (a combined index of REM latency, REM density, and REM sleep percent). Galanthamine provoked significant alterations of sleep continuity, sleep architecture (reduced SWS), and increased most of the components of REM pressure, taking patients and control subjects together. Apart from SWS %SPT (sleep period time) no significant drug-group interactions occurred. Patients who remained abstinent (n = 11) for at least 6 months at follow-up exhibited significantly less abnormalities of REM sleep at T0 compared to the group of patients that relapsed at 6 months follow-up. CONCLUSIONS: It is concluded that increased REM sleep pressure after alcohol withdrawal is a robust predictor of vulnerability to relapse. Thus, a subgroup of alcoholic patients appears to exhibit distinct neurobiological abnormalities assessable by polysomnography that are related to an increased vulnerability for alcoholism and early relapse.     

Cannabis withdrawal syndrome in patients with cannabis dependence only, and in patients with cannabis and opioid dependence

Background

The cannabis withdrawal syndrome occurs after cannabis cessation in more than 50% of dependent smokers. But although opioid-dependent patients are more frequently cannabis users and cannabis-dependent than the general population, the frequency and phenomenology of cannabis withdrawal symptoms in this specific population is unknown. Our hypothesis was that cannabis-dependent patients with current opioid dependence would experience the same withdrawal syndrome after cannabis cessation.

Objective

To describe cannabis withdrawal symptoms in cannabis-only dependent patients and in cannabis-dependent patients with current opioid dependence.

Methods

Using retrospective interviews, we evaluated the number and duration of six cannabis withdrawal symptoms in two groups: 56 cannabis-dependent patients without and 43 cannabis dependent patients with current opioid dependence. Cannabis and opioid dependence diagnoses were defined with DSM IV criteria using the MINI structured interview.

Results

The two groups were not different in terms of age of onset of cannabis use, and number of cannabis joints smoked at the time of the cannabis cessation attempt. The frequency of a cannabis withdrawal syndrome (defined as at least two different symptoms) did not differ in the two groups (65%). Neither was the proportion of subjects with the following symptoms: appetite or weight loss (30.8%), irritability (45.1%), anxiety (56%), aggression (36.3%) and restlessness (45.1%). Patients with cannabis dependence and current opioid dependence were more likely to report sleep disturbances (79.1 vs. 53.6%, chi² = 6.91, P = 0.007). The median duration of this cannabis withdrawal syndrome was 20 days post-cessation.

Conclusion

This is, to our knowledge, the first study describing cannabis withdrawal syndrome in cannabis-dependent patients with current opioid dependence. These patients experience a cannabis withdrawal syndrome as often as cannabis-only dependent subjects, but describe more frequently sleep disturbances. This high rate of sleep disturbances may cause relapse to cannabis use.     

A systematic evaluation of the DSM-III-R criteria for alcohol dependence

The diagnostic efficiency of the nine DSM-III-R criteria (signs and symptoms) for alcohol dependence was systematically investigated in a sample of 215 psychiatric outpatients. Specificity was generally greater than 0.90, but two groups of criteria were distinguished according to high v moderate sensitivity rates. The diagnostic relevance of all DSM-III-R criteria was strongly supported by a comparison with additional characteristics of alcoholism. Features referring to impaired control over alcohol use and to physical dependence (tolerance and withdrawal) were found to be most clearly discriminating between subjects with and without alcohol dependence. There is strong evidence that two positive criteria are sufficient to reliably diagnose alcohol dependence. A computer-simulated analysis was performed to demonstrate predictive power of single symptoms under different base rate conditions, and results were promising for the most common settings in clinical research.     

Cocaine and kappa-opioid withdrawal in Planaria blocked by D-, but not L-, glucose

Planarians (Dugesia dorotocephala) that were exposed for 1 h to cocaine (80 microM) or to the kappa-selective opioid receptor agonist U-50,488H (1 microM) displayed an abstinence-induced withdrawal syndrome, indicative of the development of physical dependence, when they were tested in cocaine- (or U-50,488H-) free water, but not when they were tested in cocaine- (or U-50,488H-) containing water. The withdrawal was manifested as a significant (P<0.05) decrease in the rate of planarian spontaneous locomotor activity over a 5-min observation period, using a recently designed metric. Co-exposure of the planarians to D-glucose (1 microM) or to 2-deoxy-D-glucose (2-DG, 1 microM), but not to L-glucose (1 microM), significantly attenuated (P<0.05) the development of physical dependence, shown by an attenuated withdrawal syndrome, from cocaine and U-50,488H. These results suggest that either D-glucose and 2-deoxy-D-glucose compete with a common cocaine and kappa-opioid transport mechanism or that the development of physical dependence (or the inhibition of abstinence-induced withdrawal) in planarians requires energy supplied from glucose metabolism.     

Periodic limb movements during sleep in alcohol dependent patients

Complaints of sleep disturbances are common among alcohol dependent patients during subacute abstinence. Recovered patients may show persistent sleep abnormalities for months or even years. In the present study we studied the issue whether periodic limb movements in sleep and disturbances of nocturnal respiration are more frequent in alcohol dependent patients than healthy subjects and may be of predictive value for sustained abstinence vs. relapse after withdrawal. Forty alcohol dependent patients spent three nights in the sleep laboratory at three time points: 2 to 3 weeks after withdrawal (T0) and at follow-up investigations 6 (T1) and 12 (T2) months after discharge from the hospital. Measurements of PLMS-arousal index and nocturnal respiration were performed during the first laboratory night of each measurement point. Alcohol dependent patients displayed a significantly enhanced PLMS-arousal index at T0 compared to age- and gender-matched healthy subjects, whereas no alterations of nocturnal respiration were found. The PLMS-arousal index at T0 was significantly elevated in patients who relapsed during the next 6 months compared to abstinent patients. In a discriminant function analysis the PLMS-arousal index classified 55 % of the patients correctly with respect to outcome after 6 months. It correctly predicted 80 % of abstainers and 44 % of the patients who relapsed. According to neurobiological models of the generation of PLMS and the etiopathology of alcohol dependence a genetically determined vulnerability of the dopaminergic system is discussed as a factor underlying an increased risk of relapse in a subgroup of alcohol dependent patients. Received: 14 November 2001 / Accepted: 7 May 2002     

Alterations in alcohol consumption, withdrawal seizures, and monoamine transmission in rats treated with phentermine and 5-hydroxy-L-tryptophan

We have previously shown that coadministration of the dopamine (DA) agonist phentermine plus the serotonergic agonist fenfluramine suppresses alcohol intake and withdrawal seizures in rats. In the present study, phentermine and the serotonin (5-HT) precursor, 5-hydroxy-L-tryptophan (5-HTP), were administered alone, or in combination, to rats fed on a 6% alcohol-containing diet or an isocaloric control diet. Following a 9-h withdrawal period from the alcohol-containing diet, phentermine enhanced the effects of 5-HTP on both reduction of alcohol withdrawal seizures as well as changes in striatal serotonin. Food intake was monitored for 24 h after drug treatment, and neurochemical measures were examined at various time points. Phentermine alone reduced food intake in all diet conditions, but this anorectic effect was followed by hyperphagia in control rats. Phentermine plus 5-HTP reduced the consumption of the alcohol-containing diet, while its effects on consumption of control diets were mixed. In vivo microdialysis in rat nucleus accumbens revealed that phentermine increased extracellular DA, whereas 5-HTP caused marked elevations in extracellular 5-HT. Coadministration of phentermine and 5-HTP evoked simultaneous elevations in extracellular DA and 5-HT that mirrored the effects of each drug alone. Collectively, these findings show that coadministered phentermine plus 5-HTP is effective in reducing alcohol intake and suppressing alcohol withdrawal seizures. These therapeutic actions may be related to elevations in synaptic DA and 5-HT in critical brain regions.     

Ethanol withdrawal induces hyperalgesia mediated by PKCepsilon

Symptoms of ethanol withdrawal include heightened responses to sensory stimuli, as well as tremors and convulsions. We tested the hypothesis that repeated episodes of ethanol intake and withdrawal exacerbate the symptoms of alcohol-induced peripheral neuropathy. In contrast to the hyperalgesia produced when an alcohol (6.5%)-containing diet was fed continuously to male rats which took 4 weeks to develop (Dina et al., 2000), feeding alcohol (6.5%) in repeated cycles of 4 days of alcohol followed by 3 days without alcohol resulted in a withdrawal-induced hyperalgesia that began at the end of one weekly cycle and reached a maximum during the fourth cycle. For ethanol withdrawal to produce hyperalgesia, ethanol consumption needed to be terminated for a period of 2 days. Paradoxically, as the amount of alcohol consumed decreased, the hyperalgesia induced by withdrawal developed more rapidly, being maximal between 1.4 and 1.6% ethanol. These results suggest that continued exposure to ethanol also has a neuroprotective effect. Withdrawal-induced hyperalgesia, similar to the hyperalgesia induced by continuous, chronic alcohol intake, was inhibited reversibly by intrathecal administration of an antisense oligodeoxynucleotide to protein kinase C (PKC)epsilon.     

Characteristics of Suicide Attempts Preceded by Alcohol Consumption

Acute alcohol ingestion and alcohol dependence are known to increase the risk of impulsive suicide attempt even in non-depressed patients. The relation between alcohol and suicide risk needs, however, to be clarified. We assessed for this purpose prevalence of recent alcohol intake among suicide attempters and compared suicide attempts preceded (“Alcohol + ”) or not by alcohol intake. We included 160 patients examined in the emergency service of a French general hospital after a suicide attempt. Psychiatric disorders were identified according to the DSM-IV criteria. Patients were rated for depression and alcohol use disorder (MAST). Prevalence of alcohol consumption was 40%. Patients from the “Alcohol + ” group were significantly older (40 versus 34.8 years, p = 0.03). Alcohol abuse was more frequent among suicide attempters with prior alcohol ingestion (49% versus 12%,). Alcohol dependence was also more frequent in the “Alcohol + ” group (43% versus 9%). Patients from the “Alcohol + ” group drank more alcohol each day (6.1 versus 1.3 drinks) and more often during the week (3.6 days per week versus 1.4). They had a higher number of alcohol intoxications each week (0.9 versus 0.3). They drank more often alone (41% versus 12%, p < 0.005) and in the morning (21% versus 3%). They had higher scores on the Michigan Alcohol Screening test (14.8 versus 2.9). Prevalence of drug dependence was higher in the “Alcohol + ” group (21% versus 3%, respectively). Suicide attempts must be asked about their recent alcohol intake. This alcohol intake is often the symptom of an alcohol abuse or dependence disorder.     

Cross-Sectional Associations of Lifestyle Behaviors with Depressive Symptoms in Adolescents

This study aimed to examine the associations between lifestyle behaviors and depressive symptoms in adolescents. Self-reported data from the 2019 Youth Risk Behavior Survey (YRBS) was analyzed. Depressive symptoms were set as the outcome variable. Movement variables (physical activity, muscle-strengthening exercise, physical education attendance, sports team participation, television watching, video or computer games, and sleep), eating behaviors (fruit intake, vegetable intake, milk intake, and eating breakfast or not), and substance use (alcohol use and cigarette use) were included as explanatory variables. Binary logistic regression was used to explore the associations between lifestyle behaviors and depressive symptoms after adjusting for sex, age, grade, race, and weight status. Of 13,677 participants who completed the investigation, girls were more than boys (50.3% vs. 48.6%). The proportion of participants in grades 9, 10, 11, and 12 was 26.6, 27.2, 24.3, and 20.8, respectively. Of them, the prevalence of depressive symptoms was 36.0% (weighted%: 36.7% [35.1%, 38.3%]). Among all the lifestyle behaviors included, participating in no sports teams (OR = 1.53 [1.32, 1.77]), spending more than 2 h in video or computer games (OR = 1.64 [1.40, 1.92]), sleeping less than 8 h nightly (OR = 1.79 [1.45, 2.20]), not eating breakfast (OR = 1.56 [1.37, 1.78]), alcohol use (OR = 1.74 [1.49, 2.02]), and cigarette use (OR = 1.83 [1.42, 2.37]) were associated with higher odds of depressive symptoms. To reduce depressive symptoms in adolescents, interventions can consider encouraging adolescents to engage in team sports activity, limit time for video or computer games, sleep enough, regularly eat breakfast, and avoid using alcohol and cigarette. Future studies are encouraged to verify our research findings by using a more improved study design.     

Corticotropin-releasing factor 1 antagonists selectively reduce ethanol self-administration in ethanol-dependent rats.

BACKGROUND: Alcohol dependence is characterized by excessive alcohol consumption, loss of control over intake, and the presence of a withdrawal syndrome, which includes both motivational and physical symptoms. Similar to human alcoholics, ethanol-dependent animals display enhanced anxiety-like behaviors and enhanced ethanol self-administration during withdrawal, effects hypothesized to result from a dysregulation of corticotropin-releasing factor (CRF) stress systems. Here, we used an animal model of ethanol dependence to test the effects of CRF(1) receptor antagonists on excessive ethanol self-administration in dependent rats. METHODS: Wistar rats, trained to orally self-administer ethanol, were exposed intermittently to ethanol vapors to induce ethanol dependence. Nondependent animals were exposed to control air. Following a 2-hour period of withdrawal, dependent and nondependent animals were systemically administered antalarmin, MJL-1-109-2, or R121919 (CRF(1) antagonists) and ethanol self-administration was measured. RESULTS: The nonpeptide, small molecule CRF(1) antagonists selectively reduced excessive self-administration of ethanol in dependent animals during acute withdrawal. The antagonists had no effect on ethanol self-administration in nondependent rats. CONCLUSIONS: These data demonstrate that CRF(1) receptors play an important role in mediating excessive ethanol self-administration in dependent rats, with no effect in nondependent rats. CRF(1) antagonists may be exciting new pharmacotherapeutic targets for the treatment of alcoholism in humans.     

Monoamine Oxidase Activity in Blood Platelets in Alcoholism

A newly developed assay for monoamine oxidase (MAO) activity in blood platelets was applied in 50 alcoholic patients. The assay is the direct measurement of serotonin oxidation by MAO employing a double microcolumn technique on Sephadex G-10 and Amberlite CG-50 for separating 5–HIAA formed, which is measured fluori-metrically. Rebound of MAO activity levels after withdrawal of alcohol was observed to be more pronounced in the patients with delirium tremens than those who exhibited no outstanding abstinent symptomatology. MAO activity levels measured in the 1st week of alcohol withdrawal were 3.49±1.15 (Mean±S.D.) nmol/mg protein/hour in the alcoholic patients with delirium tremens, a value significantly lower than that in the subjects without (p<0.01) and that in the male normal subjects (p<0.001). Four weeks after withdrawal of alcohol, the reduced MAO activity levels in the alcoholic population were restored to normal levels. These data demonstrate that physical dependency for alcohol occurred evidently in the alcoholic patients examined. Delirium tremens and other psychotic symptoms in alcoholism may be manifested as impaired serotonin metabolism in the brain, which may be due to MAO inhibition caused by excessive alcohol intake.     

Characteristics of suicide attempts preceded by alcohol consumption.

Acute alcohol ingestion and alcohol dependence are known to increase the risk of impulsive suicide attempt even in non-depressed patients. The relation between alcohol and suicide risk needs, however, to be clarified. We assessed for this purpose prevalence of recent alcohol intake among suicide attempters and compared suicide attempts preceded ("Alcohol + ") or not by alcohol intake. We included 160 patients examined in the emergency service of a French general hospital after a suicide attempt. Psychiatric disorders were identified according to the DSM-IV criteria. Patients were rated for depression and alcohol use disorder (MAST). Prevalence of alcohol consumption was 40%. Patients from the "Alcohol + " group were significantly older (40 versus 34.8 years, p = 0.03). Alcohol abuse was more frequent among suicide attempters with prior alcohol ingestion (49% versus 12%,). Alcohol dependence was also more frequent in the "Alcohol + " group (43% versus 9%). Patients from the "Alcohol + " group drank more alcohol each day (6.1 versus 1.3 drinks) and more often during the week (3.6 days per week versus 1.4). They had a higher number of alcohol intoxications each week (0.9 versus 0.3). They drank more often alone (41% versus 12%, p < 0.005) and in the morning (21% versus 3%). They had higher scores on the Michigan Alcohol Screening test (14.8 versus 2.9). Prevalence of drug dependence was higher in the "Alcohol + " group (21% versus 3%, respectively). Suicide attempts must be asked about their recent alcohol intake. This alcohol intake is often the symptom of an alcohol abuse or dependence disorder.     

Corticosteroid-dependent plasticity mediates compulsive alcohol drinking in rats

Alcoholism is characterized by a compulsion to seek and ingest alcohol, loss of control over intake, and the emergence of a negative emotional state during abstinence. We hypothesized that sustained activation of neuroendocrine stress systems (e.g., corticosteroid release via the hypothalamic-pituitary-adrenal axis) by alcohol intoxication and withdrawal and consequent alterations in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation drive compulsive alcohol drinking. Our results showed that rats exposed to alcohol vapor to the point of dependence displayed increased alcohol intake, compulsive drinking measured by progressive-ratio responding, and persistent alcohol consumption despite punishment, assessed by adding quinine to the alcohol solution, compared with control rats that were not exposed to alcohol vapor. No group differences were observed in the self-administration of saccharin-sweetened water. Acute alcohol withdrawal was accompanied by downregulated GR mRNA in various stress/reward-related brain regions [i.e., prefrontal cortex, nucleus accumbens (NAc), and bed nucleus of the stria terminalis (BNST)], whereas protracted alcohol abstinence was accompanied by upregulated GR mRNA in the NAc core, ventral BNST, and central nucleus of the amygdala. No significant alterations in MR mRNA levels were found. Chronic GR antagonism with mifepristone (RU38486) prevented the escalation of alcohol intake and compulsive responding induced by chronic, intermittent alcohol vapor exposure. Chronic treatment with mifepristone also blocked escalated alcohol drinking and compulsive responding during protracted abstinence. Thus, the GR system appears to be involved in the development of alcohol dependence and may represent a potential pharmacological target for the treatment of alcoholism.     

Development of a mouse model of ethanol addiction: naltrexone efficacy in reducing consumption but not craving

Summary. The aim of the present study was validating pharmacologically a mouse model of alcohol addiction. Mice (n = 60) were offered ethanol (5% and 10%) and water in a free choice paradigm consisting of four phases: free choice (10 weeks), withdrawal (2 weeks), re-exposure (2 weeks) and quinine- adulteration (2 weeks). Control mice (n = 10) had access to water. They were housed individually with food ad libitum. The animals’ behaviour was evaluated at the beginning of the treatment and during the withdrawal period. After the exposure to the model, mice received i.p. naltrexone (0.0; 0.125; 2.0 and 16.0 mg/kg) or saline. Mice were characterized as: addicted (n = 15, preference for ethanol without reducing intake when ethanol were adulterated with quinine); heavy drinker (n = 14, preference for ethanol but reduced intake when ethanol were adulterated); and light drinker (n = 16, no preference for ethanol). Naltrexone reduced ethanol intake in the heavy and light groups (p ≤ 0.01 and p ≤ 0.05, respectively, compared to saline-treated group) with no effect on water intake. It is discussed that naltrexone may be acting in the positive reinforcing properties of ethanol but does not seem to have anti-craving properties. It was concluded that the addicted mice had a compulsive behavior manifested by the continued ethanol intake even under aversive conditions and under naltrexone treatment suggesting that this model might be useful to study addiction.     

Pharmacodynamic effects of acamprosate on markers of cerebral function in alcohol-dependent subjects administered as pretreatment and during alcohol abstinence

Animal studies suggested that acamprosate modulates neuronal hyperexcitability of acute alcohol withdrawal, acting through the glutamatergic neurotransmission. In the present study, we further investigated whether treatment with acamprosate could attenuate the post-alcohol withdrawal hyperexcitability or hyperarousal in humans using brain magnetoencephalography mapping of spontaneous fields. A double-blind, randomised, placebo-controlled study with a parallel group design comparing 2,000 mg/day of acamprosate versus placebo was conducted in alcohol-dependent subjects meeting DSM-IV criteria for alcohol dependence. Treatments were initiated 8 days before alcohol withdrawal and prolonged during the 15 following (abstinence) days. The study demonstrated that during alcohol withdrawal, acamprosate decreased the arousal level as reflected by alpha slow-wave index (ASI) measurement. This effect was mostly evidenced in left parietotemporal regions and, to a lesser extent, in the contiguous anterior, posterior and right-sided regions. In the placebo group, on the contrary, ASI measures increased between day 2 (acute withdrawal) and day 14 (prolonged withdrawal). The present results suggest a sustained effect of acamprosate on the hyperexcitability state due to alcohol withdrawal in alcohol-dependent patients and that acamprosate may have a protective effect when administered 8 days before alcohol withdrawal.     

Cortical gamma-aminobutyric acid type A-benzodiazepine receptors in recovery from alcohol dependence: relationship to features of alcohol dependence and cigarette smoking

CONTEXT: Adaptations in gamma-aminobutyric acid type A (GABA(A))-benzodiazepine receptors contribute to the neurobiology of human alcohol dependence and withdrawal. OBJECTIVE: To study GABA(A)-benzodiazepine receptor adaptations in subjects with alcohol dependence over the first month of sobriety. DESIGN: Inpatients who were not receiving medication, were either smokers or nonsmokers, and had alcohol dependence completed 2 iodine I 123-labeled iomazenil single-photon emission computed tomographic scans: 1 scan at a mean +/- SD of 4.9 +/- 2.5 days of sobriety (n = 23) and 1 scan at a mean +/- SD of 29.8 +/- 7.6 days of sobriety (n = 20). Participants in a matched group of healthy subjects (n = 15) completed 1 single-photon emission computed tomographic scan. PARTICIPANTS: Men with alcohol dependence (n = 27) and a matched healthy comparison group (n = 15). MAIN OUTCOME MEASURES: (123)I-iomazenil single-photon emission computed tomographic images were converted to units of distribution volume (regional activity/free (123)I-iomazenil) and were analyzed using voxel-based statistical parametric mapping and regions of interest analyses. The relationships between (123)I-iomazenil distribution volume, clinical features of alcohol dependence, and smoking status were evaluated. RESULTS: (123)I-iomazenil uptake was elevated in several cortical regions, with a more prominent increase in nonsmokers with alcohol dependence as compared with smokers with alcohol dependence at 1 week of abstinence from alcohol. No significant differences were observed at 4 weeks of abstinence. At 1 week of abstinence, frontal (123)I-iomazenil uptake correlated with the severity of alcohol withdrawal and the number of days since the last alcoholic drink was consumed. No significant associations were observed for smokers with alcohol dependence. CONCLUSIONS: These data demonstrate time-dependent regulation of cortical GABA(A)-benzodiazepine receptors associated with the recovery from alcohol dependence. Higher GABA(A)-benzodiazepine receptor levels during acute withdrawal may reflect a compensation for reduced receptor function, which is thought to contribute to alcohol tolerance and withdrawal. The subsequent decline may reflect "normalization" of GABA(A) receptor function with sobriety. Smoking may attenuate GABA(A) receptor adaptations associated with alcohol dependence and may contribute to the comorbidity between alcoholism and smoking.