Acamprosate Suppresses Ethanol-Induced Place Preference in Mice With Ethanol Physical Dependence

Kurokawa, Kazuhiro; Mizuno, Koji; Shibasaki, Manabu; Higashioka, Masaya; Oka, Michiko; Hirouchi, Masaaki; Ohkuma, Seitaro

doi:10.1254/jphs.13056fp

Cited by 14 publications

(10 citation statements)

References 45 publications

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“…38) For the preclusive CPP protocol, Mcgeehan and Olive 12) pre-treated mice with Acam (i.p.) 10 min prior to ethanol administration during conditioning, whereas Kurokawa et al 13) administered Acam (p.o.) 1 h before the post-test for the therapeutic CPP protocol.…”

Section: Discussionmentioning

confidence: 99%

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Factors Affecting Ethanol-Induced Conditioned Place Preference and Locomotor Sensitization in Mice

Shimizu

Oki

Mitani

et al. 2015

Biological & Pharmaceutical Bulletin

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The rewarding effects of alcohol can lead to progressively heavier and more frequent drinking. Since studies of reward have mainly focused on responses to higher alcohol doses, the relations between reward and moderate/sustained alcohol exposure remain unknown. Our objective was to evaluate factors affecting the reward value of low alcohol doses and risk factors for increasing alcohol doses due to reward progression caused by alcohol exposure patterns. We thus performed conditioned place preference (CPP) and ethanol (EtOH)-induced locomotor sensitization tests in mice. Low-dose EtOH (0.5 or 1 g/kg twice/week)-induced CPP was stronger than that produced by saline control treatment, but the effect decreased with increasing numbers of conditioning trials. Moderate-dose/long-term EtOH exposure induced a weaker CPP than high-dose/short-term EtOH (2 g/kg twice/week) exposure with the same total EtOH dose (8 g/kg/experiment). Acamprosate calcium, an anti-relapse drug, preclusively reduced EtOH-induced CPP. EtOH induced CPP and locomotor sensitization in black but not white chamber, although the initial preference and the basal locomotion in each chamber were equal. Therefore the brightness of the chamber had an effect on EtOHinduced sensitization. Moreover, additional studies indicated that EtOH-induced locomotor sensitization also depends on the dose but not the administration interval. Paired associative learning with EtOH exposure is a potent factor influencing the level of reward produced by EtOH. Moreover, exposure to high doses of alcohol, even on an intermittent schedule, carries a higher risk of addiction than exposure to moderate doses over longer periods.Key words moderate alcohol (ethanol: EtOH); conditioned place preference (CPP); reward; sensitization; paired associative learning Alcohol abuse is associated with serious physical and psychiatric illnesses, financial hardships, familial dysfunction, and violence, all of which place a substantial burden on society. Heavy alcohol consumption and long-term drinking increase the risk of alcohol-related diseases such as liver cirrhosis, cancer, pancreatitis, and depression. 1,2) In response, the World Health Organization (WHO) recently approved a Global Strategy to Reduce Harmful Use of Alcohol urging all countries to strengthen national responses to public health problems caused by alcohol use.3) In Japan, 6.45 million people suffer from alcohol-related problems, with an estimated annual economic loss of 4.15 trillion yen associated with alcohol. 4) In December 2013, the Basic Act on Measures against Alcohol-related Health Harm was enacted in Japan, promoting education about drinking in moderation to prevent alcoholrelated problems.Regular consumption of alcohol increases the propensity for addiction because of the rewarding effects of alcohol. Thus, many casual drinkers gradually increase total alcohol consumption, which becomes habitual over time. Although many studies in rodents have been conducted on chronic drinking and reward, 5-7) previous studies have ma...

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Section: Discussionmentioning

confidence: 99%

“…administration 12) and therapeutically following per os (p.o.) administration, 13) to confirm the reward values of the ethanol doses tested in our CPP experiments and examined the preclusive effects of Acamprosate calcium (Acam) on EtOH-induced reward.…”

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confidence: 99%

Factors Affecting Ethanol-Induced Conditioned Place Preference and Locomotor Sensitization in Mice

Shimizu

Oki

Mitani

et al. 2015

Biological & Pharmaceutical Bulletin

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“…Mice were subjected to 30 minutes of transient focal cerebral ischemia as described below followed by intraperitoneal treatment with either acamprosate (Sigmal-Aldrich, Taufkirchen, Germany; solved in NaCl) or standard saline (control) during reperfusion, at 3, 6, 9, 12, and 24 hours after stroke. Referring to previous studies, [15][16][17][18][19][20] mice received a modified injection protocol with a single intraperitoneal injection of acamprosate at a dose of 400 mg/kg bodyweight (BW). To exclude toxic side effects of acamprosate after high dosage bolus application, analysis of potential weight loss and blood count analysis was performed 1 day before stroke induction as well as on days 7 and 14 after stroke ( Table 1).…”

Section: Experimental Paradigmmentioning

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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“…Acamprosate suppressed alcohol-induced place preference in mice with alcohol physical dependence [22]. Animal studies have also shown that acamprosate reduces some of the adverse behavioural and neurochemical events associated with alcohol withdrawal, such as hyperactivity and anxiety-like behaviour, as well as attenuation of elevated glutamate levels during the early stages after withdrawal [8].…”

Section: Pharmacodynamicsmentioning

confidence: 97%

Acamprosate: A Review of Its Use in Alcohol Dependence

Plosker

2015

Drugs

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Acamprosate (Campral(®), Aotal(®), Regtect(®)) is one of a limited number of pharmacological treatment options approved as an adjunct to psychosocial interventions to facilitate the maintenance of abstinence in alcohol-dependent patients. It has been used in Europe, the USA and other countries for many years and was recently approved for this indication in Japan. In several randomized, double-blind, placebo-controlled trials (without active comparators), acamprosate in conjunction with psychosocial therapy for 3-12 months was generally significantly better than placebo plus psychosocial interventions in improving various key outcomes, including the proportion of patients who maintained complete abstinence from alcohol (complete abstinence rate), the mean cumulative abstinence duration, the percentage of alcohol-free days and the median time to first drink. Acamprosate as an adjunct to psychosocial interventions also demonstrated efficacy in some randomized, active-comparator trials of similar duration. Although results were not always consistent across individual trials, overall findings were generally favourable for acamprosate in a recent meta-analysis, which showed that alcohol-consumption outcomes were similarly improved with acamprosate or naltrexone. Acamprosate is generally well tolerated, has a low propensity for drug interactions and may be used without dosage adjustment in patients with mild to moderate hepatic impairment, although dosage adjustments or contraindications are recommended in patients with renal impairment. Thus, the use of acamprosate as an adjunct to psychosocial interventions in alcohol-dependent patients provides modest but potentially valuable improvements in alcohol-consumption outcomes and is generally well tolerated.

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Acamprosate Suppresses Ethanol-Induced Place Preference in Mice With Ethanol Physical Dependence

Cited by 14 publications

References 45 publications

Factors Affecting Ethanol-Induced Conditioned Place Preference and Locomotor Sensitization in Mice

Factors Affecting Ethanol-Induced Conditioned Place Preference and Locomotor Sensitization in Mice

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

Acamprosate: A Review of Its Use in Alcohol Dependence

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