A homotaurine derivative reduces the voluntary intake of ethanol by rats: are cerebral GABA receptors involved?

Boismare, F; Daoust, M.; Moore, N; Saligaut, Christian; Lhuintre, J. P.; Chrétien, Pierre; Durlach, J

doi:10.1016/s0091-3057(84)80020-9

Cited by 166 publications

(65 citation statements)

References 5 publications

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“…Acamprosate has been shown in animal models to block the excessive drinking associated with deprivation, dependence, and individual differences (Gewiss et al, 1991;Boismare et al, 1984;Le Magnen et al, 1987;Spanagel et al, 1996a;Holter et al, 1997;Heyser et al, 1998), and in humans has been shown in several multicenter clinical trials to increase abstinence and prevent relapse in detoxified alcoholics (Mason, 2001). Acamprosate also has some effects in preventing aversive effects associated with ethanol withdrawal (Spanagel et al, 1996b;Cole et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Buprenorphine and a CRF1 Antagonist Block the Acquisition of Opiate Withdrawal-Induced Conditioned Place Aversion in Rats

Stinus

Cador

Zorrilla

et al. 2004

Neuropsychopharmacol

127

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Conditioned place aversion in rats has face validity as a measure of the aversive stimulus effects of opiate withdrawal that reflects an important motivational component of opiate dependence. The purpose of the present study was to validate conditioned place aversion as sensitive to medications that will alleviate the aversive stimulus effects of opiate withdrawal in humans, and to extend this model to the exploration of the neuropharmacological basis of the motivational effects of opiate withdrawal. Male Sprague-Dawley rats were implanted with two subcutaneous morphine pellets and 5 days later began place conditioning training following subcutaneous administration of a low dose of naloxone. Animals were subjected to three pairings of a low dose of naloxone (15 mg/kg, s.c.) to one arm of a three-chambered place conditioning apparatus. Buprenorphine administered prior to each pairing dose-dependently blocked the place aversion produced by precipitated opiate withdrawal. A corticotropin-releasing factor-1 (CRF 1 ) receptor antagonist (antalarmin) also reversed the place aversion produced by precipitated opiate withdrawal. Antalarmin did not produce a place preference or place aversion by itself in morphine-dependent rats. No effect was observed with pretreatment of the dopamine partial agonist terguride or the selective serotonin reuptake inhibitor fluoxetine. Also, chronic pretreatment with acamprosate (a glutamate receptor modulator used to prevent relapse in alcohol dependence) did not alter naloxone-induced place aversion. Buprenorphine by itself in dependent rats produced a mild place preference at low doses and a mild place aversion at higher doses. These results suggest that buprenorphine blocks the aversive stimulus effects of precipitated opiate withdrawal in rats and provides some validity for the use of place conditioning as a measure that is sensitive to potential opiate-dependence medications. In addition, these results suggest that CRF 1 antagonists can block the aversive stimulus effects of opiate withdrawal and may be potential therapeutic targets for opiate dependence.

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Section: Discussionmentioning

confidence: 99%

Buprenorphine and a CRF1 Antagonist Block the Acquisition of Opiate Withdrawal-Induced Conditioned Place Aversion in Rats

Stinus

Cador

Zorrilla

et al. 2004

Neuropsychopharmacol

127

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“…Since acamprosate is chemically similar to GABA, early studies indicated that acamprosate interacts with the GABAergic system [16] to affect behaviours related to ethanol consumption. However, this interaction of acamprosate with the GABA receptors does not appear to be comparable to the effects induced by either benzodiazepines or barbiturates since acamprosate cannot be substituted for GABA agonists in a drug-discrimination procedure [68].…”

Section: Acamprosatementioning

confidence: 99%

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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“…Almost 30 years ago, the inhibiting effect of acamprosate (calcium-bis(N-acetylhomotaurinate)-in the entire text abbreviated as Ca-AOTA) on alcohol consumption in laboratory animals was described (Boismare et al, 1984). This initial observation led to the clinical development of acamprosate (Campral) and nowadays this drug is currently used in many countries for relapse prevention in abstinent alcohol-dependent patients.…”

Section: Introductionmentioning

confidence: 99%

Acamprosate Produces Its Anti-Relapse Effects Via Calcium

Spanagel

Vengeliene

Jandeleit³

et al. 2013

Neuropsychopharmacol

126

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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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A homotaurine derivative reduces the voluntary intake of ethanol by rats: are cerebral GABA receptors involved?

Cited by 166 publications

References 5 publications

Buprenorphine and a CRF1 Antagonist Block the Acquisition of Opiate Withdrawal-Induced Conditioned Place Aversion in Rats

Buprenorphine and a CRF1 Antagonist Block the Acquisition of Opiate Withdrawal-Induced Conditioned Place Aversion in Rats

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

Acamprosate Produces Its Anti-Relapse Effects Via Calcium

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