Anti-craving Drug Research Articles

Plasma TNFSF10 levels associated with acamprosate treatment response in patients with alcohol use disorder.

Acamprosate is an anti-craving drug used in alcohol use disorder (AUD) pharmacotherapy. However, only a subset of patients achieves optimal treatment outcomes. The identification of predictive biomarkers of acamprosate treatment response in patients with AUD would be a substantial advance in addiction medicine. We designed this study to use proteomics data as a quantitative biological trait as a step toward identifying inflammatory modulators that might be associated with acamprosate treatment outcomes. The NIAAA-funded Mayo Clinic Center for the Individualized Treatment of Alcoholism study had previously recruited 442 AUD patients who received 3 months of acamprosate treatment. However, only 267 subjects returned for the 3-month follow-up visit and, as a result, had treatment outcome information available. Baseline alcohol craving intensity was the most significant predictor of acamprosate treatment outcomes. We performed plasma proteomics using the Olink target 96 inflammation panel and identified that baseline plasma TNF superfamily member 10 (TNFSF10) concentration was associated with alcohol craving intensity and variation in acamprosate treatment outcomes among AUD patients. We also performed RNA sequencing using baseline peripheral blood mononuclear cells from AUD patients with known acamprosate treatment outcomes which revealed that inflammation-related pathways were highly associated with relapse to alcohol use during the 3 months of acamprosate treatment. These observations represent an important step toward advancing our understanding of the pathophysiology of AUD and molecular mechanisms associated with acamprosate treatment response. In conclusion, applying omics-based approaches may be a practical approach for identifying biologic markers that could potentially predict alcohol craving intensity and acamprosate treatment response.

P55. TRAIL Protein Levels are Associated With Response to Acamprosate Therapy in Alcohol Use Disorder: A Proteomics-Based Approach

Alcohol use disorder (AUD) poses a major societal health burden. Acamprosate, an anti-craving drug, may help achieve abstinence, albeit with suboptimal response rates in a significant proportion of patients. We applied a proteomics-based approach to identify predictors of response to acamprosate therapy.

Genetic variants associated with acamprosate treatment response in alcohol use disorder patients: A multiple omics study.

Background and PurposeAcamprosate is an anti‐craving drug used for the pharmacotherapy of alcohol use disorder (AUD). However, only some patients achieve optimal therapeutic outcomes. This study was designed to explore differences in metabolomic profiles between patients who maintained sobriety and those who relapsed, to determine whether those differences provide insight into variation in acamprosate treatment response phenotypes.Experimental ApproachWe previously conducted an acamprosate trial involving 442 AUD patients, and 267 of these subjects presented themselves for a 3‐month follow‐up. The primary outcome was abstinence. Clinical information, genomic data and metabolomics data were collected. Baseline plasma samples were assayed using targeted metabolomics.Key ResultsBaseline plasma arginine, threonine, α‐aminoadipic acid and ethanolamine concentrations were associated with acamprosate treatment outcomes and baseline craving intensity, a measure that has been associated with acamprosate treatment response. We next applied a pharmacometabolomics‐informed genome‐wide association study (GWAS) strategy to identify genetic variants that might contribute to variations in plasma metabolomic profiles that were associated with craving and/or acamprosate treatment outcome. Gene expression data for induced pluripotent stem cell‐derived forebrain astrocytes showed that a series of genes identified during the metabolomics‐informed GWAS were ethanol responsive. Furthermore, a large number of those genes could be regulated by acamprosate. Finally, we identified a series of single nucleotide polymorphisms that were associated with acamprosate treatment outcomes.Conclusion and ImplicationsThese results serve as an important step towards advancing our understanding of disease pathophysiology and drug action responsible for variation in acamprosate response and alcohol craving in AUD patients.

Acamprosate—an Anti-Craving Drug for Alcohol Use Disorder (AUD) Pharmacotherapy: Plasma Metabolomics Signatures are Associated With Alcohol Craving Intensity and Acamprosate Treatment Response

Acamprosate is an anti-craving drug used for the pharmacotherapy of alcohol use disorder (AUD). However, acamprosate’s mechanism(s) of action during the treatment of AUD remains unclear, and only some patients achieve optimal therapeutic outcomes. The present study was designed to explore the differences in metabolomic profiles between patients who maintained sobriety and those who relapsed. It also sought to determine whether those differences might provide insight into the mechanisms involved in the variations in acamprosate treatment response phenotypes.

Calcium Carbonate Attenuates Withdrawal and Reduces Craving: A Randomized Controlled Trial in Alcohol-Dependent Patients

Introduction: Preclinical studies have shown that calcium seems to be the active component of the anti-craving drug acamprosate (Ca²⁺ bis-acetyl-homotaurinate). Clinical effects in humans have also indicated an association between increased calcium plasma concentration due to acamprosate treatment and better outcome relating to time to relapse and cumulative abstinence. In contrast, low calcium concentration in alcohol-dependent patients was related with craving for alcohol. The main goal of the trial was to investigate whether an oral calcium administration is able to affect craving, withdrawal, and relapse risk in alcohol-dependent patients. Methods: We conducted a single-blind, randomized, monocentric, controlled clinical two-arm trial in alcohol-dependent patients (Clinical Trials Registration: DRKS00011293). A total of 55 alcohol-dependent subjects received calcium carbonate (800 mg + 5 μg vitamin D) versus sodium bicarbonate (1,000 mg) daily during the 14 days of inpatient alcohol-withdrawal treatment. Results: Based on an intention-to-treat protocol, withdrawal intensity (assessed with CIWA-Ar) in the calcium carbonate group attenuated faster than in the sodium bicarbonate subgroup. Alcohol craving (assessed with OCDS) in the calcium carbonate subgroup was also significantly reduced versus the sodium bicarbonate subgroup. Conclusion: Our data support earlier findings and show that treatment with calcium carbonate during alcohol withdrawal reduces symptoms of alcohol withdrawal as well as alcohol craving in a controlled clinical pilot study. Mode of actions will need to be determined to allow the further development of pharmacological interventions beyond Ca²⁺ bis-acetyl-homotaurinate.

What we have learned from the Methadone Maintenance Treatment of Dual Disorder Heroin Use Disorder patients.

Mental Disorders and Heroin Use Disorder (HUD) often co-occur and constitute correlated risk factors that the authors believe are best considered from a unitary perspective. In this article we review and discuss data collected by the V.P. Dole Research Group in Dual Disorder (V.P. Dole DD-RG) patients according to the following six discussion points: (1) Treatment of personality disorders during Methadone Maintenance Treatment (MMT); (2) Treatment of Mood Disorders during MMT; (3) Treatment of Anxiety Disorders during MMT; (4) Treatment of Psychotic Disorders during MMT; (5) Treatment of violence during MMT; (6) Treatment of Alcohol Use Disorder (AUD) during MMT. In treating Mood Disorder in HUD patients, we must bear in mind the interactions (potentiation and side effects) between psychopharmacology, used substances and agonist opioid medications; the use of psychiatric medications as an anti-craving drug, and the possible use of agonist and antagonist opioid medications in treating the other mental disorders. In treating chronic psychosis in HUD patients, we must consider the potentiation and side effects of antipsychotic drugs consequent on HUD treatment, worsening addiction hypophoria and inducing a more severe reward deficiency syndrome (RDS) in hypophoric patients. Violence and AUD during MMT can benefit from adequate dosages of methadone and co-medication with Sodium gamma-hydroxybutyrate (GHB). The experience of our V.P. Dole DD-RG suggests the following: (a) DD is the new paradigm in neuroscience in deepening our understanding of mental health; (b) To successfully treat DD patients a double competence is needed; (c) In managing DD patients priority must be given to Substance Use Disorder (SUD) treatment (stabilizing patients); (d) Antidepressant use is ancillary to SUD treatment; antipsychotic use must be restricted to acute phases; mood stabilizers must be preferred; any use of Benzodiazepines (BDZs) must be avoided.

Multidisciplinary View of Alcohol Use Disorder: From a Psychiatric Illness to a Major Liver Disease.

Alcohol use disorder is a significant health problem being a cause of increased morbidity and mortality worldwide. Alcohol-related illness has a relevant economic impact on the society and a negative influence on the life of patients and their family members. Psychosocial support might be useful in the management of people affected by alcohol use disorder since psychiatric and pharmaceutical approaches show some limits. In fact, many drugs are accessible for the treatment of alcohol disorder, but only Baclofen is functional as an anti-craving drug in patients with advanced liver disease. The alcohol-related liver damage represents the most frequent cause of advanced liver disease in Europe, and it is the main cause of death among adults with high alcohol consumption. The multidisciplinary action of clinical-psychologists, psychiatrics and hepatologists, is essential in the management of patients with alcohol liver disease especially in the case of liver transplantation. In general, the multidisciplinary approach is necessary in prevention, in framing patients and in the treatment. More resources should be used in prevention and research with the main aim of decreasing the harmful alcohol consumption.

The clinical pharmacology of acamprosate

Acamprosate is one of the few medications licensed for prevention of relapse in alcohol dependence, and over time it has proved to be significantly, if moderately, effective, safe and tolerable. Its use is now being extended into other addictions and neurodevelopmental disorders. The mechanism of action of acamprosate has been less clear, but in the decade or more that has elapsed since its licensing, a body of translational evidence has accumulated, in which preclinical findings are replicated in clinical populations. Acamprosate modulates N-methyl-d-aspartic acid receptor transmission and may have indirect effects on γ-aminobutyric acid type A receptor transmission. It is known to decrease brain glutamate and increase β-endorphins in rodents and man. Acamprosate diminishes reinstatement in ethanolized rodents and promotes abstinence in humans. Although acamprosate has been called an anticraving drug, its subjective effects are subtle and relate to diminished arousal, anxiety and insomnia, which parallel preclinical findings of decreased withdrawal symptoms in animals treated with acamprosate. Further understanding of the pharmacology of acamprosate will allow appropriate targeting of therapy in individuals with alcohol dependence and extension of its use to other addictions.

Involvement of mGlu5 and NMDA receptors in the antidepressant-like effect of acamprosate in the tail suspension test

Accumulating evidence supports the hypothesis that modulation of glutamatergic system via NMDA receptors and mGlu5 receptors might be an effective antidepressant therapy. However, clinical application of NMDA and mGlu5 antagonists in the therapy of depression is still an open question. In the present study we investigated potential antidepressant-like effect of a functional NMDA and mGlu5 receptor antagonist, acamprosate, which has been used in the therapy of human alcoholics as an anti-craving drug for more than 20 years and is considered as a safe substance. We have found potential antidepressant-like effect of acamprosate at doses of 100-400 mg/kg in the TST in C57BL/6J mice. Furthermore we have shown that the antidepressant-like effect of acamprosate used at a dose of 200 mg/kg was dependent on NMDA and mGlu5 receptor blockade, since NMDA (25 mg/kg) and mGlu5 receptor positive allosteric modulator, CDPPB (3 mg/kg), antagonized its activity in the TST. These data suggest that acamprosate may induce antidepressant-like effect and that NMDA and mGlu5 receptors are crucial targets of acamprosate in this action.

Un dispositif de prescriptions hors-AMM : exemple du baclofène

Baclofen is an anti-spastic drug that acts as an agonist of GABA-B receptors. It also seems to decrease the appetence for alcohol (anti-craving effect), although this effect has not been certified by Authorities for drug approval in France (AMM). However, baclofen receives a great deal of demand by patients hoping to reduce their alcohol consumption. Nonetheless, the lack of AMM and the high doses of baclofen supposed to exert an anti-craving effect often discourage practitioners from prescribing this drug in current medical practice. Therefore, it is preferable for a drug like baclofen to be prescribed under specific regulations. As such, certain criteria similar to those required in clinical trials are necessary to protect patients as well as the prescribing doctors. The criteria that are proposed here are: the use of drugs without AMM approval as a last resort (all other treatments must have failed), the collegiate decision for the drug prescription, good knowledge of the potency of the drug as well as good record keeping of patients and proper supervision. The departments of addiction, pharmacology and pharmacovigilance of the University Hospital of Lille, France present here a medical process named "multidisciplinary consultations for resort treatments of addictions" (CAMTEA). This process is designed to meet all the above mentioned criteria and to allow the use of baclofen as an anti-craving drug in safest conditions. If this proves to be successful with baclofen, it is possible to extend the use of CAMTEA to other drugs without AMM approval in addictologic pathologies.

Adherence with naltrexone prescription advice in hospital outpatient alcohol rehabilitation programme

Background: The anti-craving drug, naltrexone, is used as a pharmacotherapeutic adjunct in the treatment of alcohol dependence. In addictive disorders, compliance issues remain central. There are limited data on compliance with naltrexone treatment regimens within formalized rehabilitation programs and even less data that identifies factors that have an impact on this. Objective: To study patient adherence to naltrexone medication regimens and examine whether patients’ reported pre-treatment alcohol use, dependence severity and measures of psychological health are predictive of medication compliance. Method: Fifty outpatients meeting DSM IV criteria for alcohol dependence enrolled in a 12-week rehabilitation programme. This included cognitive behavioural therapy (CBT) and naltrexone, 50 mg orally daily. Measures included: pharmacy prescription pick-up including number of tablets dispensed, programme attendance and patient pre-treatment alcohol use variables. Measures of psychological health included somatic symptoms, anxiety, social dysfunction and depression as measured by the General Health Questionnaire (GHQ-28). Results: Classifying the sample into compliant (≥90% medication pick-up) and less compliant groups, 66% of subjects were naltrexone-compliant. Pre-treatment alcohol use variables were not predictive of compliance. Although social dysfunction and depression tended towards poorer prescription filling, measures of psychological distress (GHQ-28) did not identify factors predictive of medication non-compliance. One patient withdrew from treatment because of naltrexone-induced dysphoria. Conclusion: Patients with alcohol dependence demonstrated high levels of anti-craving medication compliance, good rehabilitation programme participation and favourable outcomes. Naltrexone was well tolerated. Medication compliance in this study group compared well with those of other hospital populations with chronic disorders. Factors predictive of anti-craving medication compliance in alcohol dependence require further study.

Flupenthixol in Relapse Prevention in Schizophrenics with Comorbid Alcoholism: Results from an Open Clinical Study

Substance use, especially alcoholism, has been recognized as a significant problem in schizophrenic patients, though only a few studies on the effects of pharmacotherapy in these patients have been conducted so far. The thioxanthene neuroleptic flupenthixol, which can be given intramuscularly (i.m.) for improving compliance, has been studied as a possible anti-craving drug both in animal models of alcoholism and some clinical studies. Pilot studies suggest that comorbid schizophrenics with substance use may benefit from treatment with flupenthixol. Efficacy of flupenthixol (10–60 mg i.m.) in reducing alcohol consumption of dual diagnosis patients was studied in an open 6-month clinical trial in 27 schizophrenics with comorbid alcoholism. Twenty-one patients entered the intention-to-treat analysis. Fourteen subjects were completers, 13 dropped out. Six patients completely abstained from alcohol during treatment. Alcohol consumption was significantly reduced compared to baseline (4 weeks before treatment as measured by timeline follow-back interview). In general, while patients showed a marked improvement concerning alcohol consumption, only a slight improvement in psychopathology was recorded. Overall tolerability was good. These data indicate a probable beneficial effect of flupenthixol in schizophrenic patients with comorbid alcoholism. Although the efficacy of flupenthixol as an anti-craving drug in dual diagnosis patients has to be explored in further studies, the drug may be considered a promising medication for these patients.

Adherence with naltrexone prescription advice in hospital outpatient alcohol rehabilitation programme.

The anti-craving drug, naltrexone, is used as a pharmacotherapeutic adjunct in the treatment of alcohol dependence. In addictive disorders, compliance issues remain central. There are limited data on compliance with naltrexone treatment regimens within formalized rehabilitation programs and even less data that identifies factors that have an impact on this. To study patient adherence to naltrexone medication regimens and examine whether patients' reported pre-treatment alcohol use, dependence severity and measures of psychological health are predictive of medication compliance. Fifty outpatients meeting DSM IV criteria for alcohol dependence enrolled in a 12-week rehabilitation programme. This included cognitive behavioural therapy (CBT) and naltrexone, 50 mg orally daily. Measures included: pharmacy prescription pick-up including number of tablets dispensed, programme attendance and patient pre-treatment alcohol use variables. Measures of psychological health included somatic symptoms, anxiety, social dysfunction and depression as measured by the General Health Questionnaire (GHQ-28). Classifying the sample into compliant (> or = 90% medication pick-up) and less compliant groups, 66% of subjects were naltrexone-compliant. Pre-treatment alcohol use variables were not predictive of compliance. Although social dysfunction and depression tended towards poorer prescription filling, measures of psychological distress (GHQ-28) did not identify factors predictive of medication non-compliance. One patient withdrew from treatment because of naltrexone-induced dysphoria. Patients with alcohol dependence demonstrated high levels of anti-craving medication compliance, good rehabilitation programme participation and favourable outcomes. Naltrexone was well tolerated. Medication compliance in this study group compared well with those of other hospital populations with chronic disorders. Factors predictive of anti-craving medication compliance in alcohol dependence require further study.

Intracerebroventricular injection of antisense oligos to nNOS decreases rat ethanol intake

Nitric oxide (NO) has been implicated in alcohol drinking behavior using NO synthase (NOS) inhibitors that are nonselective of the different isoforms of NOS. In the brain, there are two constitutive isoforms of NOS, neuronal NOS (nNOS) and endothelial NOS (eNOS). We used an antisense oligodeoxynucleotide directed against nNOS in ethanol dependent male Wistar rats to examine the specific contribution of nNOS in the control of ethanol intake. Rats were subjected to a free-choice situation water/ethanol (10% v/v) after chronic ethanol intoxication by inhalation of ethanol vapor. During the free-choice situation, rats were twice daily for 4 days intracerebroventricularly injected with either saline, or end-capped phosphorothioate-protected antisense or mismatch oligodeoxynucleotide (25 μg/4 μl per injection), or acamprosate (1 mg/kg body weight) as reference product for its anticraving properties. Our results showed that the antisense treatment, but not the mismatch treatment, reduced both ethanol intake and ethanol preference during treatment and posttreatment periods (by 25–30%) without alteration of the body weight gain. The antisense treatment, but not the mismatch treatment, also down-regulated nNOS mRNA levels (by 30%) and NOS activity in the hippocampus. The anticraving drug, acamprosate reduced both ethanol intake (by 58%) and ethanol preference. All these results suggest that nNOS is involved in the regulation of alcohol dependence.

Flupenthixol as a potential pharmacotreatment of alcohol and cocaine abuse/dependence

Preclinical and clinical studies suggest that the mesolimbic dopamine system plays a major role in mediating the reinforcing effects of drugs of abuse, including alcohol and psychostimulants, and that pharmacological blockade of dopamine D1 and/or D2 receptors may reduce intake of these drugs, as well as relapse rates. The neuroleptic flupenthixol, which has dopamine D1 and D2 receptor antagonist properties and which may be given intramuscularly in order to improve compliance, has been studied as a possible anti-craving drug in substance abuse disorders. Flupenthixol has been shown to attenuate the discriminative stimulus effects of psychostimulants, as well as their intake in animal models of drug abuse. In addition, the compound was found to reduce alcohol intake in a rat model of alcoholism, but the ‘anti-alcohol’ effect appeared to be only weakly selective and nonspecific. Clinically, the drug has been studied in alcoholics, cocaine addicts and in patients with comorbid psychiatric disorders. Although the data base is still limited and a number of recent trials have not been completely analyzed, these studies suggest that flupenthixol may be useful in decreasing cocaine consumption. Recent studies in alcoholism, however, have shown disappointing results. A number of pilot studies suggest that probably the most promising area may be the treatment of substance abuse/dependence in patients with comorbid psychiatric disorders. Future studies should focus on dosing issues, the differentiation between short- and long-term effects and the identification of subgroups of patients with particular psychopathology.

The anti-craving drug acamprosate inhibits the conditioned place aversion induced by naloxone-precipitated morphine withdrawal in rats

The anti-craving drug acamprosate (Ca N-acetylhomotaurinate) is therapeutically used to prevent a relapse in weaned alcoholics. In the present place conditioning study, the effect of this compound on the motivational impact of morphine withdrawal was examined. Withdrawal was precipitated in rats by administration of the opioid antagonist naloxone (0.1 mg/kg, s.c.) 5–6 days after the subcutaneous implantation of a 75 mg morphine pellet. Aversion against the naloxone-paired cues was observed after conditioning in the drug-free state. The acquisition of conditioned place aversion was completely inhibited by the pretreatment with acamprosate (200 mg/kg, i.p.) 12 h and 30 min prior to conditioning. These results clarify that acamprosate inhibits the motivational component of morphine withdrawal and suggest that ethanol and opiates share similar properties in the neuronal mechanisms of conditioned withdrawal and craving.

Mechanism of Action of Acamprosate. Part I. Characterization of Spermidine-Sensitive Acamprosate Binding Site in Rat Brain

It has been suggested that the anticraving drug, acamprosate, acts via the glutamatergic system, but the exact mechanism of action is still unknown. The aim of this study was to characterize [3H]acam-prosate binding and establish whether this showed any relation to sites on the NMDA receptor complex. We found saturable specific binding of [3H]acamprosate to rat brain membranes with a KD of 120 μM and a Bmax of 450 pmol/mg of protein. This acamprosate binding site was sensitive to inhibition by spermidine (IC50: 13.32 ± 1.1 μM; Hill coefficient = 1.04), and arcaine and glutamate both potentiated the inhibitory effect of spermidine. Acamprosate binding to the acamprosate binding site was also sensitive to inhibition by divalent cations (Ca2+, Mg2+, and Sr2+). Conversely, acamprosate displaced [14C]spermidine binding from rat brain membranes with an IC50, of 645 μM and a Hill coefficient = 1.74. This inhibitory effect of acamprosate was not affected by arcaine, and was associated with a significant reduction in Bmax and binding affinity for spermidine, suggesting an allosteric interaction between acamprosate and a spermidine binding site. These data are consistent with an effect of acamprosate on the NMDA receptor protein complex, and acamprosate was also found to alter binding of [3H]dizocilpine to rat brain membranes. When no agonists were present in vitro (minimal NMDA receptor activation), acamprosate markedly potentiated [3H]dizocilpine binding at concentrations in the 5 to 200 μ range. However, under conditions of maximal receptor activation (100 μM glutamate, 30 μM glycine), acamprosate only inhibited [3H]dizocilpine binding (at concentrations concentrations > 100 μM). When these binding studies were performed in the presence of 1 μM spermidine, the enhancing effects of acamprosate on [3H]dirocilpine binding were inhibited. The results show that acamprosate binds to a specific spermidine-sensitive site that modulates the NMDA receptor in a complex way. Together, with data from al Quatari et al. (see next paper), this work suggests that acamprosate acts as “partial co-agonist“ at the NMDA receptor, so that low concentrations enhance activation when receptor activity is low, whereas higher concentrations are inhibitory to high levels of receptor activation. This may be relevant to the clinical effects of acamprosate in alcohol-dependent patients during abstinence.

Mechanism of Action of Acamprosate. Part I. Characterization of Spermidine‐Sensitive Acamprosate Binding Site in Rat Brain

It has been suggested that the anticraving drug, acamprosate, acts via the glutamatergic system, but the exact mechanism of action is still unknown. The aim of this study was to characterize [3H]acamprosate binding and establish whether this showed any relation to sites on the NMDA receptor complex. We found saturable specific binding of [3H]acamprosate to rat brain membranes with a KD of 120 microM and a Bmax of 450 pmol/mg of protein. This acamprosate binding site was sensitive to inhibition by spermidine (IC50: 13.32 +/- 1.1 microM; Hill coefficient = 1.04), and arcaine and glutamate both potentiated the inhibitory effect of spermidine. Acamprosate binding to the acamprosate binding site was also sensitive to inhibition by divalent cations (Ca2+, Mg2+, and Sr2+). Conversely, acamprosate displaced [14C]spermidine binding from rat brain membranes with an IC50 of 645 microM and a Hill coefficient = 1.74. This inhibitory effect of acamprosate was not affected by arcaine, and was associated with a significant reduction in Bmax and binding affinity for spermidine, suggesting an allosteric interaction between acamprosate and a spermidine binding site. These data are consistent with an effect of acamprosate on the NMDA receptor protein complex, and acamprosate was also found to alter binding of [3H]dizocilpine to rat brain membranes. When no agonists were present in vitro (minimal NMDA receptor activation), acamprosate markedly potentiated [3H]dizocilpine binding at concentrations in the 5 to 200 microM range. However, under conditions of maximal receptor activation (100 microM glutamate, 30 microM glycine), acamprosate only inhibited [3H]dizocilpine binding (at concentrations concentrations >100 microM). When these binding studies were performed in the presence of 1 microM spermidine, the enhancing effects of acamprosate on [3H]dizocilpine binding were inhibited. The results show that acamprosate binds to a specific spermidine-sensitive site that modulates the NMDA receptor in a complex way. Together, with data from al Quatari et al. (see next paper), this work suggests that acamprosate acts as "partial co-agonist" at the NMDA receptor, so that low concentrations enhance activation when receptor activity is low, whereas higher concentrations are inhibitory to high levels of receptor activation. This may be relevant to the clinical effects of acamprosate in alcohol-dependent patients during abstinence.

The anti-craving drug acamprosate reduces c- fos expression in rats undergoing ethanol withdrawal

Acamprosate (Ca salt of N-acetylhomotaurine) is a novel anti-craving substance which a double-blind placebo-controlled study has proven to be therapeutically useful in the prevention of relapses in weaned alcoholics. In the present study the expression of the immediate-early gene c- fos in rat hippocampal and cerebellar neurons was used to monitor the modulatory effect of acamprosate on neuronal excitability during ethanol withdrawal. Several hybridization techniques were employed to investigate the effect of acamprosate on c- fos expression. Acamprosate (200 mg/kg; intraperitoneally) reduced the elevated c- fos mRNA levels in the hippocampus and the cerebellum following 24 h of ethanol withdrawal, or the application of the convulsant pentylenetetrazole. The effect of ethanol withdrawal on c- fos expression was more pronounced in the cerebellum than in the hippocampus. In the hippocampus (CA1) and the cerebellum acamprosate alone induced a significant increase in c- fos expression in drug-naive animals. Only in the hippocampus did co-administration of pentylenetetrazole during ethanol withdrawal induce a further increase in c- fos expression. The present findings support the notion that acamprosate elicits its preventive effect on relapse by reducing the hyperexcitability of central neurons during withdrawal, following long-term ethanol consumption.

Evidence for alcohol anti-craving properties of memantine

Rats consuming alcohol voluntarily for a long time show increased alcohol consumption after a phase of alcohol deprivation and this might reflect increased craving for alcohol. Administration of memantine (1-amino-3,5-dimethyl-adamantane), a clinically used uncompetitive NMDA receptor antagonist, resulted in a significant reduction of the alcohol deprivation effect without any sedative, dysphoric or stimulant side-effects. The dose of memantine used (4.8 mg/day) resulted in serum levels close to the therapeutic range in humans. These results indicate that memantine may have therapeutic potential as an anti-craving drug for alcohol.