Preclinical evaluation of riluzole: assessments of ethanol self-administration and ethanol withdrawal symptoms.

BACKGROUND: Many of the neurobehavioral effects of ethanol are mediated by inhibition of excitatory N-methyl-D-aspartate (NMDA) and enhancement of inhibitory gamma-amino-butyric-acid (GABA) receptor systems. There is growing interest in drugs that alter these systems as potential medications for problems associated with alcoholism. The drug riluzole, approved for treatment of amyotrophic lateral sclerosis (ALS), inhibits NMDA and enhances GABA(A) receptor system activity. This study was designed to determine the preclinical efficacy of riluzole to modulate ethanol self-administration and withdrawal. METHODS: Male C57BL/6J mice were trained to lever press on a concurrent fixed-ratio 1 schedule of ethanol (10% v/v) versus water reinforcement during daily 16-hour sessions. Riluzole (1 to 40 mg/kg, IP) was evaluated on ethanol self-administration after acute and chronic (2 week) treatment. To determine if riluzole influences ethanol withdrawal-associated seizures, mice were fed an ethanol-containing or control liquid diet for 18 days. The effects of a single injection of riluzole (30 mg/kg) were examined on handling-induced convulsions after ethanol withdrawal. RESULTS: Acute riluzole (30 and 40 mg/kg) reduced ethanol self-administration during the first 4 hours of the session, which corresponds to the known pharmacokinetics of this drug. Ethanol self-administration was also reduced by riluzole after chronic treatment. Riluzole (30 mg/kg) significantly decreased the severity of ethanol-induced convulsions 2 hours after ethanol withdrawal. CONCLUSIONS: These results demonstrate that riluzole decreases ethanol self-administration and may reduce ethanol withdrawal severity in mice. Thus, riluzole may have utility in the treatment of problems associated with alcoholism.

Alcohol withdrawal syndrome: how to predict, prevent, diagnose and treat it.

(1) When people who are physically dependent on alcohol stop drinking, they experience an alcohol withdrawal syndrome. The symptoms generally resolve spontaneously within a week, but more severe forms may be associated with generalised seizures, hallucinations and delirium tremens, which can be fatal. (2) We carried out a literature review in order to obtain answers to the following questions: how to predict or rapidly diagnose a severe alcohol withdrawal syndrome; how to prevent and treat this syndrome; how to manage severe forms; and how to deal with the risk of vitamin B1 deficiency. (3) The main risk factors for severe withdrawal syndrome are: chronic heavy drinking; a history of generalised seizures; and a history of delirium tremens. (4) Anxiety, agitation, tremor, excessive sweating, altered consciousness and hallucinations are signs of a severe withdrawal syndrome. (5) Individual support and effective communication seem to reduce the risk of severe withdrawal syndrome. (6) Oral benzodiazepines are the best-assessed drugs for preventing a severe alcohol withdrawal syndrome, particularly the risk of seizures. When given for a maximum of 7 days, the adverse effects are usually mild. (7) Clinical trials of other antiepileptics suggest they are less effective than benzodiazepines, and their addition to benzodiazepine therapy offers no tangible advantage. (8) Betablockers increase the risk of hallucinations, and clonidine increases the risk of nightmares, and the efficacy of these two drugs is not well documented. Neuroleptics increase the risk of seizures. There are no convincing data to support the use of magnesium sulphate or meprobamate (the latter carries a risk of serious adverse effects). Acamprosate, naltrexone and disulfiram are not beneficial in alcohol withdrawal. (9) Gradual withdrawal, i.e. ingestion of decreasing amounts of alcohol, has not been compared with other methods but is generally not recommended. (10) There are no specific recommendations on hydration. Note that excessive water-sodium intake carries a risk of pulmonary oedema in patients with heart disease. (11) As vitamin B1 deficiency is frequent and can lead to serious complications in alcohol-dependent patients, oral vitamin B1 supplementation is widely recommended, despite the absence of comparative trials. High doses must be used to compensate for poor absorption. Intravenous administration is best if patients have very poor nutritional status or severe complications such as Gayet-Wernicke encephalopathy (a medical emergency), even though rare anaphylactic reactions have been reported after vitamin B1 injection. (12) Planned alcohol withdrawal in specialised hospital units has been extensively studied. Outpatient withdrawal may be more appropriate for patients who are at low risk of developing severe withdrawal syndrome. (13) A large proportion of alcohol-dependent patients were excluded from trials of withdrawal strategies. These include elderly patients, patients with serious psychiatric or somatic disorders, and patients who are also dependent on other substances. (14) An oral benzodiazepine is the best-assessed treatment for a single episode of generalised seizures or hallucinations during alcohol withdrawal. (15) In randomised comparative trials benzodiazepines were more effective than neuroleptics in preventing delirium-related mortality. Currently, with appropriate fluid-electrolyte support, continuous monitoring of vital signs, and respiratory support if necessary, the mortality rate for delirium tremens is under 3%. (16) In practice, patients who are attempting to stop drinking alcohol need close personal support and communication, and a reassuring environment, as well as regular monitoring for early signs of a withdrawal syndrome; the latter may require benzodiazepine therapy.

Protective effect of quercetin on alcohol abstinence-induced anxiety and convulsions.

Chronic administration of ethanol (2 g/kg, p.o.) on days 1-6 and its withdrawal produced an anxiogenic reaction in mice as assessed in the mirrored-chamber test. Daily administration of quercetin (25 or 50 mg/kg, p.o.) prior to ethanol for 6 days prevented withdrawal-induced anxiety in mice. However, acute administration of a single dose of quercetin (50 mg/kg) to animals withdrawn from ethanol, i.e., on day 7, did not prevent withdrawal-induced anxiety. Ethanol withdrawal also induced a significant increase in the locomotor activity of mice indicating an anxiogenic response. Daily administration of quercetin (25 or 50 mg/kg, p.o.) prior to ethanol for 6 days prevented withdrawal-induced increased locomotor activity. Ethanol withdrawal also sensitized the convulsogenic reaction to pentylenetetrazole (PTZ). A non-convulsive dose (40-60 mg/kg) of PTZ produced full-blown convulsions and increased mortality in ethanol-withdrawn mice. Both acute and chronic administration of quercetin (25 or 50 mg/kg, p.o.) produced a significant protection against ethanol withdrawal-induced reduction in PTZ threshold in mice. The result suggests the protective effect of this safe drug, quercetin, in the management of ethanol withdrawal reactions.

[Folate against hyperhomocysteinemia. A new approach for the prevention and therapy of alcoholism-associated disorders?]. / Folsäure gegen Hyperhomocysteinämie. Ein neuer Ansatz zur Prävention und Therapie Alkoholismus-bedingter Störungen?

There is growing evidence that chronic alcoholism is associated with a derangement in the sulfur amino acid metabolism. Excitatory aminoacids such as glutamate, aspartate, and homocysteine have been shown to be increased in patients with chronic alcoholism who underwent alcohol withdrawal. Furthermore, sustained hyperhomocysteinemia occurred in chronic alcoholics with active drinking pattern. Excitotoxicity can be induced by increased hormocysteine levels via rebound activation of NMDA receptor-mediated glutamatergic neurotransmission upon the removal of ethanol-evoked inhibition. Therefore, hyperhomocysteinemia may be responsible for the higher incidence of complications during alcohol withdrawal (e.g.stroke,convulsions). In addition, an association between brain atrophy and increased levels of homocysteine in chronic alcoholism was shown. This may have important implications for the pathogenesis of brain atrophy in alcoholics. Taking into account that high plasma homocysteine levels are helpful in the prediction of alcohol withdrawal seizures, early anti-convulsive therapy could prevent this severe complication. Supplementation of folate, a cofactor of the homocysteine metabolism, lowers raised homocysteine levels and therefore could be established as a new therapeutic strategy in alcohol withdrawal treatment. The results of various studies highlight the need for further research to prove whether alcoholics benefit from a reduced homocysteine level with respect to both, alcohol-related disorders and alcohol withdrawal symptoms.