Mechanism of Action of Acamprosate. Part I. Characterization of Spermidine-Sensitive Acamprosate Binding Site in Rat Brain
ABSTRACT 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.
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ABSTRACT: Historically, most pharmacological approaches to the treatment of addictive disorders have utilized either substitution-based methods (i.e., nicotine replacement or opioid maintenance) or have targeted monoaminergic or endogenous opioidergic neurotransmitter systems. However, substantial evidence has accumulated indicating that ligands acting on glutamatergic transmission are also of potential utility in the treatment of drug addiction, as well as various behavioral addictions such as pathological gambling. The purpose of this review is to summarize the pharmacological mechanisms of action and general clinical efficacy of glutamatergic medications that are currently approved or are being investigated for approval for the treatment of addictive disorders. Medications with effects on glutamatergic transmission that will be discussed include acamprosate, N-acetylcysteine, d-cycloserine, gabapentin, lamotrigine, memantine, modafinil, and topiramate. We conclude that manipulation of glutamatergic neurotransmission is a relatively young but promising avenue for the development of improved therapeutic agents for the treatment of drug and behavioral addictions.Pharmacology Biochemistry and Behavior 04/2011; 100(4):801-10. DOI:10.1016/j.pbb.2011.04.015 · 2.82 Impact Factor
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ABSTRACT: This article explores the mechanisms of action and the potential responder profile of acamprosate, a compound efficacious in relapse prevention of alcoholism. New evidence at the molecular and cellular level suggests that acamprosate attenuates hyper-glutamatergic states that occur during early abstinence and involves iono (NMDA)- and metabotrotropic (mGluR5) glutamate receptors along with augmented intracellular calcium release and electrophysiological changes. Thus mutant mice with enhanced glutamate levels exhibit higher alcohol consumption than wild type mice and respond better to acamprosate, demonstrating that acamprosate acts mainly on a hyper-glutamatergic system. This mode of action further suggests that acamprosate exhibits neuroprotective properties. In rats, cue-induced reinstatement behavior is significantly reduced by acamprosate treatment whereas cue-induced craving responses in alcohol-dependent patients seem not to be affected by this treatment. An ongoing study ("Project Predict") defines specific responder profiles for an individualized use of acamprosate and naltrexone. Neurophysiological as well as psychometric data are used to define 2 groups of patients: "reward cravers" and "relief cravers". While naltrexone should work better in the first group, acamprosate is hypothesized to be efficacious in the latter where withdrawal associated and/or cue induced hyper-glutamatergic states are thought to trigger relapse. Further research should target the definition of subgroups applying endophenotypic approaches, e.g. by detecting a hyperglutamatergic syndrome using MR spectroscopy.Alcoholism Clinical and Experimental Research 08/2008; 32(7):1105-10. DOI:10.1111/j.1530-0277.2008.00690.x · 3.31 Impact Factor
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ABSTRACT: Acamprosate and naltrexone are widely used in the treatment of alcoholism. However, numerous studies in rodents have shown differential effects of these compounds on alcohol consumption and/or relapse-like behavior following acute versus repeated administration. In order to determine if these differential behavioral effects could be attributable to changes in extracellular levels of these compounds, we used in vivo microdialysis to monitor extracellular levels of acamprosate and naltrexone in the rat medial prefrontal cortex following acute and repeated intraperitoneal administration. For acute treatment, animals received a single administration of acamprosate (100 or 300 mg/kg) or naltrexone (1 or 3 mg/kg). For repeated treatment, animals received once daily treatment with saline, acamprosate (300 mg/kg) or naltrexone (3 mg/kg) for 10 days before a subsequent challenge with the compound according to their respective pretreatment group. Dialysate levels of acamprosate and naltrexone were analyzed by liquid chromatography-tandem mass spectrometry and high performance liquid chromatography, respectively. Following acute administration, peak dialysate concentrations of each compound were dose-dependent, observed within 1 hour of administration, and were found to be in the low micromolar range for acamprosate and in the low to mid-nanomolar range for naltrexone. Pretreatment with acamprosate, but not naltrexone, for 10 days resulted in higher dialysate concentrations of the compound relative to saline-pretreated controls. Thus, repeated administration of acamprosate, but not naltrexone, results in augmented extracellular levels of the compound in the brain relative to saline-pretreated controls, which may explain the need for repeated administration of acamprosate in order to observe effects on alcohol consumption and/or relapse.Addiction Biology 04/2008; 13(1):70-9. DOI:10.1111/j.1369-1600.2008.00097.x · 5.93 Impact Factor