Hölter SM, Danysz W, Spanagel R. Novel uncompetitive N-methyl-D-Aspartate (NMDA)-receptor antagonist MRZ 2/579 suppresses ethanol intake in long-term ethanol-experienced rats and generalizes to ethanol cue in drug discrimination procedure. J Pharmacol Exp Ther 292: 545-552

Max Planck Institute of Psychiatry, Munich, Germany.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 03/2000; 292(2):545-52.
Source: PubMed


Previous findings suggested that drugs modulating glutamatergic neurotransmission could be useful in the treatment of alcohol dependence. This study examined the effects of chronic and acute treatment with MRZ 2/579 (1-amino-1,3,3,5,5-pentamethyl-cyclohexane hydrochloride), a novel uncompetitive N-methyl-D-aspartate receptor antagonist, on voluntary ethanol intake in long-term ethanol-experienced rats. Rats were implanted with mini-osmotic pumps delivering either 9.6 mg/day MRZ 2/579 or vehicle, and the effects of treatment on the alcohol deprivation effect (ADE) were studied in a four-bottle home cage-drinking paradigm. The same rats were tested for a second ADE 3 weeks later in the absence of the drug. In a second experiment long-term ethanol-experienced rats trained in an operant free-choice ethanol self-administration paradigm with concurrent water received acute MRZ 2/579 treatment (0-4 mg/kg i.p.) before a 23-h session either during basal drinking or during the ADE. In an additional experiment, MRZ 2/579 (0.5-4 mg/kg i.p.) was tested for generalization to the ethanol cue in a drug discrimination procedure. Chronic MRZ 2/579 treatment selectively abolished the increased ethanol intake during the ADE. This effect depended on the presence of the drug. Acute MRZ 2/579 treatment (2 and 4 mg/kg) had a short-lasting reductive effect on lever pressing for ethanol, but not for water, both during the ADE and basal drinking. MRZ 2/579 dose dependently generalized to the ethanol cue in the drug discrimination experiment. It is concluded that MRZ 2/579 might exert its reducing effect on ethanol intake by substituting for some of the stimulus properties of ethanol.

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    • "Data from animal studies confirmed the efficiency of NMDA antagonists in reducing alcohol consumption and craving. The noncompetitive NMDA receptor antagonist MRZ2/579, has been shown to suppress ethanol intake in long-term ethanol-experienced rats (Hölter, Danysz & Spanagel 2000) and to reduce operant ethanol self-administration (Bienkowski et al. 2001). Injections of the competitive NMDA antagonist AP-5 in the nucleus accumbens decreased ethanol self-administration in rats (Rassnick, Pulvirenti & Koob 1992). "
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    ABSTRACT: Alcoholism is a chronic relapsing disorder with consequences on health and that requires more effective treatments. Among alternative therapies, the therapeutic potential of the non-competitive N-methyl-D-aspartate receptor antagonist memantine has been suggested. Despite promising results, its efficiency in the treatment of alcoholism remains controversial. Currently, there is no pre-clinical data regarding its effects on the motivation for ethanol in post-dependent (PD) animals exposed to intermittent ethanol vapor, a validated model of alcoholism. Thus, the objectives of this study were to evaluate the effects of acute injections of memantine (0, 12.5, 25 and 50 mg/kg) on operant ethanol self-administration in non-dependent (ND) and PD rats tested either during acute withdrawal or relapse after protracted abstinence. Our results showed that memantine (25 mg/kg) abolished ethanol self-administration in ND rats and reduced by half the one of PD rats during acute withdrawal. While this effect was observed only 6 hours after treatment in ND rats, it was long lasting in PD rats (at least 30 hours after injection). Furthermore, our results indicated that memantine did not modify the breaking point for ethanol. This suggests that memantine probably act by potentiating the pharmacological effect of ethanol but not by reducing motivation for ethanol. Finally, memantine was also ineffective in reducing relapse after protracted abstinence. Altogether, our pre-clinical results highlighted a potential therapeutic use of memantine that may be used as a replacement therapy drug but not as relapse-preventing drug.
    Full-text · Article · Aug 2014 · Addiction Biology
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    • "ADE is considered a temporary increase in ethanol intake after periods of deprivation (for review, see Le and Shaham, 2002). The ADE was found to be dependent on cycles of deprivation and the duration of the deprivation period (Heyser et al., 1997; Sinclair et al., 1973; Spanagel and Holter, 2000). It is noteworthy that studies have shown that ADE was associated with increased ethanol intake in Wistar and P rats, but no ADE was observed in high-alcohol-drinking (HAD) and ALKO-alcohol (AA) rats after deprivation (Vengeliene et al., 2003). "
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    ABSTRACT: Relapse-like ethanol-drinking behavior depends on increased glutamate transmission in the mesocorticolimbic motive circuit. Extracellular glutamate is regulated by a number of glutamate transporters. Of these transporters, glutamate transporter 1 (GLT1) is responsible for the majority of extracellular glutamate uptake. We have recently reported that ceftriaxone (CEF) treatment (i.p.), a β-lactam antibiotic known to elevate GTL1 expression, reduced ethanol intake in male alcohol-preferring (P) rats. We investigated here whether CEF treatment attenuates relapse-like ethanol-drinking behavior. P rats were exposed to free choice of 15% and 30% ethanol for 5 weeks and treated with CEF (50 and 100 mg/kg, i.p.) during the last 5 days of the 2-week deprivation period. Rats treated with CEF during the deprivation period showed a reduction in ethanol intake compared with saline-treated rats upon re-exposure to ethanol; this effect persisted for 9 days. Moreover, CEF-mediated attenuation in relapse to ethanol-drinking behavior was associated with upregulation of GLT1 level in prefrontal cortex and nucleus accumbens core. GLT1 upregulation was revealed only at the higher dose of CEF. In addition, CEF has no effect on relapse-like sucrose-drinking behavior. These findings suggest that ceftriaxone might be used as a potential therapeutic treatment for the attenuation of relapse-like ethanol-drinking behavior.
    Full-text · Article · Mar 2013 · Journal of Psychopharmacology
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    • "When ethanol is reintroduced, there is a temporary increase in ethanol intake (Khisti et al., 2006). This increase in consumption is referred to as the alcohol deprivation effect (ADE) (Spanagel and Holter, 2000). This effect has been demonstrated in rats selectively bred for high ethanol drinking (HAD-1, HAD-2), with a twofold increase in consumption levels after four cycles of ethanol deprivation (Rodd et al., 2009). "
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    ABSTRACT: Despite years of neurobiological research that have helped to identify potential therapeutic targets, we do not have a reliable pharmacological treatment for alcoholism. There are a range of possible explanations for this failure, including arguments that alcoholism is a spectrum disorder and that different population subtypes may respond to different treatments. This view is supported by categorisations such as early- and late-onset alcoholism, whilst multifactorial genetic factors may also alter responsivity to pharmacological agents. Furthermore, experience of alcohol withdrawal may play a role in future drinking in a way that may distinguish alcoholism from other forms of addiction. Additionally, our neurobiological models, based largely upon results from rodent studies, may not mimic specific aspects of the human condition and may reflect different underlying phenomena and biological processes from the clinical pattern. As a result, potential treatments may be targeting inappropriate aspects of alcohol-related behaviours. Instead, we suggest a more profitable approach is (a) to identify well-defined intermediate behavioural phenotypes in human experimental models that reflect defined aspects of the human clinical disorder and (b) to develop animal models that are homologous with those phenotypes in terms of psychological processes and underlying neurobiological mechanisms. This review describes an array of animal models currently used in the addiction field and what they tell us about alcoholism. We will then examine how established pharmacological agents have been developed using only a limited number of these models, before describing some alternative novel approaches to achieving homology between animal and human experimental measures.
    Full-text · Article · Apr 2011 · British Journal of Pharmacology
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