The anti-craving compound acamprosate acts as a weak NMDA-receptor antagonist, but modulates NMDA-receptor subunit expression similar to memantine and MK-801

Rammes, Gerhard; Mahal, Beatrice; Putzke, Jörg; Parsons, Chris G.; Spielmanns, Peter; Pestel, E; Spanagel, Rainer; Zieglgänsberger, W.; Schadrack, Jan

doi:10.1016/s0028-3908(01)00008-9

Cited by 141 publications

(98 citation statements)

References 38 publications

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“…103 Furthermore, acamprosate, which can reduce relapse rates in alcoholics, also acts as an NMDA receptor antagonist (although it is not clear to what extent this particular mechanism contributes to the clinical efficacy of acamprosate since its NMDA-antagonistic potency is only weak and it has numerous other pharmacological effects). 104 Until now, the major stumbling blocks in the therapeutic use of NMDA receptor antagonists were their psychotomimetic and potentially neurotoxic effects. Furthermore, the high-affinity NMDA receptor channel blocker dizocilpine (MK-801) was shown to induce relapse to cocaine-seeking by itself, 105 suggesting that only antagonists with lowto-moderate potency may yield the desired therapeutic effect in the absence of untolerable side effects.…”

Section: Discussionmentioning

confidence: 99%

Glutamatergic mechanisms in addiction

2003

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Traditionally, addiction research in neuroscience has focused on mechanisms involving dopamine and endogenous opioids. More recently, it has been realized that glutamate also plays a central role in processes underlying the development and maintenance of addiction. These processes include reinforcement, sensitization, habit learning and reinforcement learning, context conditioning, craving and relapse. In the past few years, some major advances have been made in the understanding of how glutamate acts and interacts with other transmitters (in particular, dopamine) in the context of processes underlying addiction. It appears that while many actions of glutamate derive their importance from a stimulatory interaction with the dopaminergic system, there are some glutamatergic mechanisms that contribute to addiction independent of dopaminergic systems. Among those, context-specific aspects of behavioral determinants (ie control over behavior by conditioned stimuli) appear to depend heavily on glutamatergic transmission. A better understanding of the underlying mechanisms might open new avenues to the treatment of addiction, in particular regarding relapse prevention.

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Section: Discussionmentioning

confidence: 99%

Glutamatergic mechanisms in addiction

2003

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“…Further, no shift in affinity was noted in concentration response curves for glycine or glutamate, indicating no apparent antagonist activity in our assay. Rammes et al (2001) reported that acamprosate acts as a weak antagonist against NMDA-induced currents in Xenopus oocytes expressing NR1A/2B receptors. Testing acamprosate as the calcium salt also adds excess calcium to the preparation.…”

Section: Calcium and Acamprosate R Spanagel Et Almentioning

confidence: 99%

“…Therefore, Rammes et al (2001) tested in addition the effects of equimolar calcium concentrations and found that in four out of the eight cells tested, calcium also decreased NMDA-induced currents and a pronounced effect of acamprosate was only seen in these four cells. Thus, it seems that even the effects of high concentrations of acamprosate on NMDA receptors are not due to acamprosate itself, but rather due to nonspecific effects of calcium ions added (Rammes et al, 2001) Altogether, a detailed review of published reports and our data demonstrate that acamprosate exhibits neither agonistic nor antagonistic effects on NMDA receptors. However, there is a limitation to this conclusion, namely that in our Xenopus oocyte test system, we expressed only one possible combination (hNR1A/hNR2B) and cannot exclude the possibility that other NMDA receptor subunit compositions would yield different results.…”

Section: Calcium and Acamprosate R Spanagel Et Almentioning

confidence: 99%

“…Many molecular candidate targets have been described (Spanagel and Vengeliene, 2013;De Witte et al, 2005;Mann et al, 2008) but the only accumulated evidence was found with respect to an interaction with the glutamate system. In concert, these studies suggest that acamprosate attenuates hyperglutamatergic states that occur during early and protracted abstinence, possibly involving N-methyl-D-aspartate (NMDA) receptors and metabotropic glutamate receptor 5 (mGluR5) (Spanagel and Vengeliene, 2013;De Witte et al, 2005;Mann et al, 2008;Rammes et al, 2001;Harris et al, 2002). A prominent theory in the alcohol research field posits that chronic alcohol consumption leads to glutamatergic dysfunction.…”

Section: Introductionmentioning

confidence: 99%

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Acamprosate Produces Its Anti-Relapse Effects Via Calcium

Spanagel

Vengeliene

Jandeleit³

et al. 2013

Neuropsychopharmacol

130

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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 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 acamprosatelike 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.

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“…10,11 In this context, acamprosate inhibits NMDAR stimulation, albeit these effects are indirect only. [12][13][14] In addition to the aforementioned effects during alcohol dependence, experimental evidence suggests a therapeutic role for acamprosate in neurologic disorders such as multiple sclerosis. 15 Since activation of the glutamatergic system and stimulation of NMDAR are decisive in the development of cerebral ischemia as stated afore, a single study analyzed the therapeutic potential of acamprosate in a rat model of cerebral ischemia.…”

Section: Introductionmentioning

confidence: 99%

The Indirect NMDAR Antagonist Acamprosate Induces Postischemic Neurologic Recovery Associated with Sustained Neuroprotection and Neuroregeneration

Doeppner

Pehlke

Kaltwasser

et al. 2015

J Cereb Blood Flow Metab

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Cerebral ischemia stimulates N-methyl-D-aspartate receptors (NMDARs) resulting in increased calcium concentration and excitotoxicity. Yet, deactivation of NMDAR failed in clinical studies due to poor preclinical study designs or toxicity of NMDAR antagonists. Acamprosate is an indirect NMDAR antagonist used for patients with chronic alcohol dependence. We herein analyzed the therapeutic potential of acamprosate on brain injury, neurologic recovery and their underlying mechanisms. Mice were exposed to cerebral ischemia, treated with intraperitoneal injections of acamprosate or saline (controls), and allowed to survive until 3 months. Acamprosate yielded sustained neuroprotection and increased neurologic recovery when given no later than 12 hours after stroke. The latter was associated with increased postischemic angioneurogenesis, albeit acamprosate did not stimulate angioneurogenesis itself. Rather, increased angioneurogenesis was due to inhibition of calpain-mediated pro-injurious signaling cascades. As such, acamprosate-mediated reduction of calpain activity resulted in decreased degradation of p35, increased abundance of the pro-survival factor STAT6, and reduced N-terminal-Jun-kinase activation. Inhibition of calpain was associated with enhanced stability of the blood-brain barrier, reduction of oxidative stress and cerebral leukocyte infiltration. Taken into account its excellent tolerability, its sustained effects on neurologic recovery, brain tissue survival, and neural remodeling, acamprosate is an intriguing candidate for adjuvant future stroke treatment.

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The anti-craving compound acamprosate acts as a weak NMDA-receptor antagonist, but modulates NMDA-receptor subunit expression similar to memantine and MK-801

Cited by 141 publications

References 38 publications

Glutamatergic mechanisms in addiction

Glutamatergic mechanisms in addiction

Acamprosate Produces Its Anti-Relapse Effects Via Calcium

The Indirect NMDAR Antagonist Acamprosate Induces Postischemic Neurologic Recovery Associated with Sustained Neuroprotection and Neuroregeneration

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