Interaction of acamprosate with ethanol and spermine on NMDA receptors in primary cultured neurons

Popp, R. Lisa; Lovinger, David M.

doi:10.1016/s0014-2999(00)00195-3

Cited by 81 publications

(61 citation statements)

References 27 publications

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“…As acamprosate reversed the potentiating effects of spermine, it was thought that acamprosate may act at the polyamine site of the NMDA receptor [171]. Indeed, acamprosate effectively reduced both the enhanced glutamate-induced calcium entry and neurotoxicity in ethanol pre-treated primary cultures of organotypic hippocampal [133] or neocortical neurons from rats in a concentration-dependent manner (Fig.…”

Section: Acamprosatementioning

confidence: 91%

“…H alcohol dependent male C57BL/6J mice [171]. The expression of spontaneous ethanol withdrawal signs (piloerection, jerk, tremor) occurring 6 -12 hours after the discontinuation of ethanol treatment was suppressed by ifenprodil.…”

Section: Rgh-1103mentioning

confidence: 96%

“…Furthermore, although acamprosate significantly reduced the calcium entry caused by glutamate or K + in control and ethanol-exposed cultures, the neuroprotective effects of the drug did not correlate with its effects on calcium entry, making it unlikely that acamprosate directly affects NMDA receptors via the glutamate binding site or the receptoroperated calcium channel [4]. This idea was confirmed by further studies which found that acamprosate has no direct effect on the NMDARs [4, 132,153,171,196]. Al Qatari et al [3] argued that acamprosate may have an excitatory or inhibitory effect on NMDA receptors depending upon the experimental conditions indicating that acamprosate, at least partly, acts as a `partial agonist' at the NMDA receptor.…”

Section: Acamprosatementioning

confidence: 99%

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Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Nagy

Kolok²,

Boros³

et al. 2005

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Long-term alcohol exposure gives rise to development of physical dependence on alcohol in consequence of changes in certain neurotransmitter functions. Accumulating evidence suggests that the glutamatergic neurotransmitter system, especially the N-methyl-D-aspartate (NMDA) type of glutamate receptors is a particularly important site of ethanol's action, since ethanol is a potent inhibitor of the NMDA receptors (NMDARs) and prolonged ethanol exposition leads to a compensatory "upregulation" of NMDAR mediated functions supposedly contributing to the occurrence of ethanol tolerance, dependence as well as the acute and delayed signs of ethanol withdrawal.Recently, expression of different types of NMDAR subunits was found altered after long-term ethanol exposure. Especially, the expression of the NR2B and certain splice variant forms of the NR1 subunits were increased in primary neuronal cultures treated intermittently with ethanol. Since NMDA ion channels with such an altered subunit composition have increased permeability for calcium ions, increased agonist sensitivity, and relatively slow closing kinetics, the abovementioned alterations may underlie the enhanced NMDAR activation observed after long-term ethanol exposure. In accordance with these changes, the inhibitory potential of NR2B subunit-selective NMDAR antagonists is also increased, demonstrating excellent potency against alcohol withdrawal-induced in vitro cytotoxicity. Although in vivo data are few with these compounds, according to the effectiveness of the classic NMDAR antagonists in attenuation, not only the physical symptoms,but also some affective and motivational components of alcohol withdrawal, novel NR2B subunit selective NMDAR antagonists may offer a preferable alternative in the pharmacotherapy of alcohol dependence.

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Section: Acamprosatementioning

confidence: 91%

Section: Rgh-1103mentioning

confidence: 96%

Section: Acamprosatementioning

confidence: 99%

See 1 more Smart Citation

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Nagy

Kolok²,

Boros³

et al. 2005

View full text Add to dashboard Cite

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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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“…Thus, each of these changes produced by acamprosate may contribute to the decreased hyperexcitability observed during ethanol withdrawal and abstinence (Dahchour et al, 1998). Therefore, it has been hypothesized that acamprosate may minimize or negate some of the physiological changes produced by chronic ethanol exposure (Popp and Lovinger, 2000).…”

Section: Introductionmentioning

confidence: 99%

Effects of Naltrexone Alone and In Combination With Acamprosate on the Alcohol Deprivation Effect in Rats

Heyser

Moc

Koob

2003

Neuropsychopharmacol

101

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Previous research in our laboratory has shown that responding for ethanol increases after a period of imposed deprivation during which no ethanol is available (the alcohol deprivation effect). This selective increase in responding for ethanol was blocked by chronic administration of acamprosate. In the present study the effects of naltrexone and the combination of naltrexone+acamprosate on oral ethanol self-administration were examined following an imposed period of abstinence. Male Wistar rats were trained to respond for ethanol (10% w/v) or water in a two-lever free-choice condition. After training, separate groups of rats received chronic injections (2 Â /day) of saline, naltrexone, or naltrexone+acamprosate during a 5-day period of abstinence. Ethanol self-administration was tested in all groups of rats on the last day of abstinence, 30 min after the last drug injection. Responding for ethanol increased significantly following the deprivation period in animals treated with saline. Chronic administration of naltrexone and the combination naltrexone+acamprosate blocked the increased ethanol consumption following the imposed abstinence period on post-deprivation Day 1. On post-deprivation Day 2, the combination of acamprosate with naltrexone blocked the rebound increase in ethanol consumption observed in animals treated with a low dose of naltrexone. These results support the hypothesis that naltrexone and acamprosate are effective in modulating aspects of alcohol-seeking behavior, and under certain situations may be more effective in combination.

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Interaction of acamprosate with ethanol and spermine on NMDA receptors in primary cultured neurons

Cited by 81 publications

References 27 publications

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

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

Effects of Naltrexone Alone and In Combination With Acamprosate on the Alcohol Deprivation Effect in Rats

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