Mechanism of Action of Acamprosate. Part I. Characterization of Spermidine-Sensitive Acamprosate Binding Site in Rat Brain
INSERM U 295, UFR de Médecine-Pharmacie de Rouen, Saint Etienne Rouvray, France.Alcoholism Clinical and Experimental Research (Impact Factor: 3.21). 06/1998; 22(4):802-9. DOI: 10.1097/00000374-199806000-00005
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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- "Although its precise mechanisms of action are still unknown (Kiefer and Mann, 2010; Spanagel et al., 2014), evidence suggests that acamprosate restores the balance between excitatory and inhibitory amino acid neurotransmission that gets disrupted by chronic alcohol consumption (Dahchour and De Witte, 2003; De Witte, 2004; Kiefer and Mann, 2010). Specifically, acamprosate may attenuate hyperglutamatergic states that occur during early withdrawal by modulating transmission at both NMDA and mGluR5 glutamate receptors, and by augmenting intracellular calcium release (Al Qatari et al., 1998; Dahchour et al., 1998; Harris et al., 2002; Naassila et al., 1998). However, there is evidence that the modulatory effects of acamprosate on behavior are in fact not due to a direct interaction with NMDARs, but instead can be mimicked by elevations in calcium levels alone (Spanagel et al., 2014). "
ABSTRACT: The medial prefrontal cortex (mPFC) inhibits impulsive and compulsive behaviors that characterize drug abuse and dependence. Acamprosate is the leading medication approved for the maintenance of abstinence, shown to reduce craving and relapse in animal models and human alcoholics. Whether acamprosate can modulate executive functions that are impaired by chronic ethanol (EtOH) exposure is unknown. Here we explored the effects of acamprosate on an attentional set-shifting task and tested whether these behavioral effects are correlated with modulation of glutamatergic synaptic transmission and intrinsic excitability of mPFC neurons. We induced alcohol dependence in mice via chronic intermittent EtOH (CIE) exposure in vapor chambers and measured changes in alcohol consumption in a limited access 2-bottle choice paradigm. Impairments of executive function were assessed in an attentional set-shifting task. Acamprosate was applied subchronically for 2 days during withdrawal before the final behavioral test. Alcohol-induced changes in cellular function of layer 5/6 pyramidal neurons, and the potential modulation of these changes by acamprosate, were measured using patch clamp recordings in brain slices. Chronic EtOH exposure impaired cognitive flexibility in the attentional set-shifting task. Acamprosate improved overall performance and reduced perseveration. Recordings of mPFC neurons showed that chronic EtOH exposure increased use-dependent presynaptic transmitter release and enhanced postsynaptic N-methyl-d-aspartate receptor function. Moreover, CIE treatment lowered input resistance, and decreased the threshold and the after hyperpolarization of action potentials, suggesting chronic EtOH exposure also impacted membrane excitability of mPFC neurons. However, acamprosate treatment did not reverse these EtOH-induced changes cellular function. Acamprosate improved attentional control of EtOH exposed animals, but did not alter the concurrent changes in synaptic transmission or membrane excitability of mPFC neurons, indicating that these changes are not the pharmacological targets of acamprosate in the recovery of mPFC functions affected by chronic EtOH exposure. Copyright © 2015 by the Research Society on Alcoholism.
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- "However, some investigators have found no effect of acamprosate on NMDA-mediated synaptic transmission in the CA1 region of the hippocampus (Popp and Lovinger, 2000), while others have found that acamprosate actually potentiates NMDA receptor function in the CA1 region of the hippocampus (Madamba et al., 1996) and in the nucleus accumbens (Berton et al., 1998). Despite these inconsistent electrophysiological findings, binding studies have confirmed an interaction of acamprosate with the spermidine-, glutamate-and/or MK-801-sensitive binding site of the NMDA receptor (al Qatari et al., 1998; Harris et al., 2002; Naassila et al., 1998), and as such acamprosate is often referred to nonspecifically as an " NMDA modulator " (Figure 1). Although the precise molecular target(s) of acamprosate are still not firmly established (Kiefer and Mann, 2010; Reilly et al., 2008), most current theories posit that acamprosate restores the imbalances between excitatory and inhibitory amino acid neurotransmission that result from chronic alcohol consumption (De Witte et al., 2005; Kiefer and Mann, 2010; Spanagel et al., 2005; Umhau et al., 2010). "
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.
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- "The reason for the recent focus on glutamate results from early electrophysiological studies in cortical neurons which identified inhibitory effects of acamprosate on glutamate responses that were consistent with a weak NMDAR antagonism (Zeise et al., 1993). Radioligand binding studies suggested that acamprosate had weak partial agonist effects on NMDA receptors through indirect actions on a polyamine site on the NMDAR complex (Al Qatari et al., 1998; Naassila et al., 1998). Such a mechanism might enhance or inhibit NMDAR function depending on the local concentration of endogenous polyamines and ⁄ or the regional distribution of different subunits of the NMDAR. "
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.
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