Drugs for Relapse Prevention of Alcoholism – 10 Years of Progress

Department of Psychopharmacology and Department of Addictive Behaviour and Addiction Medicine at the Central Institute of Mental Health, Mannheim, Germany.
Trends in Pharmacological Sciences (Impact Factor: 11.54). 04/2008; 29(3):109-15. DOI: 10.1016/
Source: PubMed


Multiple neurochemical pathways are involved in mediating craving and relapse to alcohol. Opioidergic and glutamatergic systems have a key role in alcoholism, as demonstrated by the clinically effective compounds naltrexone and acamprosate acting through these systems. The dopaminergic system has long featured in alcoholism research; hitherto disappointing results from clinical studies could improve following the discovery that dopamine D3 receptor antagonism produces consistent and robust results in preclinical studies. Corticotropin-releasing factor signalling and the endocannabinoid system integrate stress-related events and thereby mediate relapse behaviour. Overall, these new targets have yielded several compounds that are undergoing clinical testing. However, the heterogeneity in treatment response makes it necessary to characterize genetic and protein markers and endophenotypes for individualized pharmacotherapy.

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    • "In light of the major implications of this study, we initiated an independent blinded replication of our findings in another laboratory (Lawrence group at Florey Institute of Neuroscience & Mental Health, University of Melbourne). Alcohol-preferring rats have been used for decades to study excessive alcohol consumption and the efficacy of putative pharmacological interventions (Spanagel and Kiefer, 2008; Bell et al, 2006). In particular, iP rats self-administering alcohol show sensitivity to acamprosate treatment (Cowen et al, 2005). "
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    ABSTRACT: Alcoholism is one of the most prevalent neuropsychiatric diseases, having an enormous health and socioeconomic impact. Along with a few other medications, acamprosate (Campral(®)-calcium-bis (N-acetylhomotaurinate) is clinically used in many countries for relapse prevention. Although there is accumulated evidence suggesting that acamprosate interferes with the glutamate system, the molecular mode of action still remains undefined. Here we show that acamprosate does not interact with proposed glutamate receptor mechanisms. In particular, acamprosate does not interact with NMDA receptors or metabotropic glutamate receptor group I. In three different preclinical animal models of either excessive alcohol drinking, alcohol-seeking or relapse-like drinking behavior we then demonstrate that N-acetylhomotaurinate by itself is not an active psychotropic molecule. Hence the sodium salt of N-acetylhomotaurinate (i) is ineffective in alcohol-preferring rats to reduce operant responding for ethanol, (ii) is ineffective in alcohol-seeking rats in a cue-induced reinstatement paradigm, (iii) and is ineffective in rats with an alcohol deprivation effect. Surprisingly, calcium salts produce acamprosate-like effects in all three animal models. We conclude that calcium is the active moiety of acamprosate. Indeed, when translating these findings to the human situation we found that patients with high plasma calcium levels due to acamprosate treatment showed better primary efficacy parameters such as time to relapse and cumulative abstinence. We conclude that N-acetylhomotaurinate is a biologically inactive molecule and that the effects of acamprosate described in more than 450 published original investigations and clinical trials and 1.5 million treated patients can possibly be attributed to calcium.Neuropsychopharmacology accepted article preview online, 30 September 2013. doi:10.1038/npp.2013.264.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 09/2013; 39(4). DOI:10.1038/npp.2013.264 · 7.05 Impact Factor
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    • "Although numerous microdialysis studies have examined the alcohol-induced glutamate release process, its concentration-dependency is less clear. It is further proposed that through various neuroadaptive responses that restore homeostasis, chronic alcohol consumption leads to an enhanced activity of the glutamatergic system in alcohol-dependent individuals (Tsai and Coyle, 1998; Spanagel and Kiefer, 2008; Ding et al., 2012). This glutamate-induced hyperexcitability within the CNS is uncovered during alcohol withdrawal. "
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    ABSTRACT: Purpose In recent years in vivo microdialysis has become an important method in research studies investigating the alterations of neurotransmitters in the extracellular fluid of the brain. Based on the major involvement of glutamate and γ-aminobutyric acid (GABA) in mediating a variety of alcohol effects in the mammalian brain, numerous microdialysis studies have focused on the dynamical behavior of these systems in response to alcohol. Methods Here we performed multiple meta-analyses on published datasets from the rat brain: (i) we studied basal extracellular concentrations of glutamate and GABA in brain regions that belong to a neurocircuitry involved in neuropsychiatric diseases, especially in alcoholism (Noori et al., Addict Biol 17:827-864, 2012); (ii) we examined the effect of acute ethanol administration on glutamate and GABA levels within this network and (iii) we studied alcohol withdrawal-induced alterations in glutamate and GABA levels within this neurocircuitry. Results For extraction of basal concentrations of these neurotransmitters, datasets of 6932 rats were analyzed and the absolute basal glutamate and GABA levels were estimated for 18 different brain sites. In response to different doses of acute ethanol administration, datasets of 529 rats were analyzed and a non-linear dose response (glutamate and GABA release) relationship was observed in several brain sites. Specifically, glutamate in the nucleus accumbens shows a decreasing logarithmic dose response curve. Finally, regression analysis of 11 published reports employing brain microdialysis experiments in 104 alcohol-dependent rats reveals very consistent augmented extracellular glutamate and GABA levels in various brain sites that correlate with the intensity of the withdrawal response were identified. Conclusions In summary, our results provide standardized basal values for future experimental and in silico studies on neurotransmitter release in the rat brain and may be helpful to understand the effect of ethanol on neurotransmitter release. Furthermore, this study illustrates the benefit of meta-analyses using the generalization of a wide range of preclinical data.
    05/2013; 1(1). DOI:10.1186/2193-9616-1-7
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    • "Drugs marketed for the treatment of alcohol dependence in Serbia are disulfiram, naltrexone and acamprosate. Choice of medication depends on physical co-morbidities, mainly liver function, temperament, typology and patients' motivation (Spanagel and Kiefer, 2008; Vyssoki et al., 2010). Naltrexone and acamprosate are not reimbursed, which limits their use. "
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    ABSTRACT: Aims: To support the Serbian Expert Board in setting up reimbursement for modern pharmacotherapeutic support, we compared a Serbian sample of alcohol-dependent patients with an Austrian sample, in order to detect differences that might inhibit the introduction of anti-craving medications in Serbia. Methods: One hundred and twenty-seven (116 males) alcohol-dependent patients in Serbia and 136 in Austria (78 males) were enrolled consecutively from January 2011 to March 2012 and were assessed using the Lesch alcoholism typology instrument (LAT). Results: Age of onset was slightly higher in the Austrian sample (28.5 vs. 30.0; P = 0.10). The Serbian sample showed a higher rate of anxiety disorders than the Austrian sample (89.8 vs. 26.5%, P ≤ 0.0001). Suicidal tendencies, independent of alcohol intake or withdrawal syndrome, were higher in the Austrian sample (1.6 vs. 13.2% P ≤ 0.0001). There was no difference between the two samples in Lesch-Type IV (26 vs 28); there was a slight excess in the Serbian sample of Type I (15 vs. 10). In Austria, significantly more Type II patients (32 vs. 52) had been included, while the Serbian sample comprised significantly more Type III patients. Conclusions: Austrian and Serbian patients are quite similar, without any showing any factor that would detract from the potential value of modern anti-craving medications in Serbia. The differences in anxiety disorders might be due to the 1990s war and should be investigated further.
    Alcohol and Alcoholism 03/2013; 48(4). DOI:10.1093/alcalc/agt011 · 2.89 Impact Factor
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