Reinstatement of ethanol-seeking behavior by drug cues following single versus multiple ethanol intoxication in the rat: effects of naltrexone.
ABSTRACT A positive relationship exists between chronic ethanol intoxication experiences and the severity of neural hyperactivity and withdrawal seizures. An important possibility is that withdrawal reactions also influence the motivation to obtain and consume ethanol.
To test this hypothesis, the effects of ethanol-cues on the recovery of extinguished ethanol-seeking and the reversal of this effect by naltrexone, were determined in non-dependent rats and in rats subjected to single versus repeated ethanol intoxications.
Rats were trained to self-administer and discriminate between 10% ethanol and water. Instrumental responding then was extinguished and the effects of exposure to ethanol and water cues were determined. Subsequently, rats were divided into three groups and exposed to control vapor (CTRL), to 12-day ethanol vapor prior to withdrawal (SW), or to three cycles of 3-day intoxication experiences (MW), respectively. Following intoxication, reacquisition and breaking point for ethanol self-administration and cues-induced reinstatement of drug-seeking were investigated.
Ethanol cues significantly reinstated responding in the pre- and post-dependence test, but no significant differences between groups was observed. However, the ability of naltrexone to attenuate the response-reinstatement was significantly reduced in MW rats. Moreover, in the progressive ratio schedule, the breaking points for ethanol were significantly increased in the MW animals.
The results suggest that repeated intoxication did not enhance cue-induced reinstatement of ethanol-seeking. However, naltrexone effects on cues-induced "relapse" appear to be attenuated in MW rats.
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ABSTRACT: Inbred mouse strains provide significant opportunities to understand the genetic mechanisms controlling ethanol-directed behaviors and neurobiology. They have been specifically employed to understand cellular mechanisms contributing to ethanol consumption, acute intoxication, and sensitivities to chronic effects. However, limited ethanol consumption by some strains has restricted our understanding of clinically relevant endpoints such as dependence-related ethanol intake. Previous work with a novel tastant-substitution procedure using monosodium glutamate (MSG or umami flavor) has shown that the procedure greatly enhances ethanol consumption by mouse strains that express limited drinking phenotypes using other methods. In the current study, we employ this MSG-substitution procedure to examine how ethanol dependence, induced with passive vapor inhalation, modifies ethanol drinking in C57BL/6J and DBA/2J mice. These strains represent ‘high’ and ‘low’ drinking phenotypes, respectively. We found that the MSG substitution greatly facilitates ethanol drinking in both strains, and likewise, ethanol dependence increased ethanol consumption regardless of strain. However, DBA/2J mice exhibited greater sensitivity dependence-enhanced drinking, as represented by consumption behaviors directed at lower ethanol concentrations and relative to baseline intake levels. DBA/2J mice also exhibited significant withdrawal-associated anxiety-like behavior while C57BL/6J mice did not. These findings suggest that the MSG-substitution procedure can be employed to examine dependence-enhanced ethanol consumption across a range of drinking phenotypes, and that C57BL/6J and DBA/2J mice may represent unique neurobehavioral pathways for developing dependence-enhanced ethanol consumption.Alcohol 01/2015; 49(2). DOI:10.1016/j.alcohol.2015.01.003 · 2.04 Impact Factor
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ABSTRACT: Introduction: Globally, alcohol abuse and dependence are significant contributors to chronic disease and injury and are responsible for nearly 4% of all deaths annually. Acamprosate (Campral), one of only three pharmacological treatments approved for the treatment of alcohol dependence, has shown mixed efficacy in clinical trials in maintaining abstinence of detoxified alcoholics since studies began in the 1980s. Yielding inconsistent results, these studies have prompted skepticism.Areas covered: Herein, the authors review the preclinical studies which have assessed the efficacy of acamprosate in various animal models of alcohol dependence and discuss the disparate findings from the major clinical trials. Moreover, the authors discuss the major limitations of these preclinical and clinical studies and offer explanations for the often-contradictory findings. The article also looks at the importance of the calcium moiety that accompanies the salt form of acamprosate and its relevance to its activity.Expert opinion: The recent discovery that large doses of calcium largely duplicate the effects of acamprosate in animal models has introduced a serious challenge to the widely held functional association between this drug and the glutamate neurotransmission system. Future research on acamprosate or newer pharmacotherapeutics should consider assessing plasma and/or brain levels of calcium as a correlate or mediating factor in anti-relapse efficacy. Further, preclinical research on acamprosate has thus far lacked animal models of chemical dependence on alcohol, and the testing of rodents with histories of alcohol intoxication and withdrawal is suggested.Expert Opinion on Drug Discovery 09/2014; 9(11). DOI:10.1517/17460441.2014.960840 · 3.47 Impact Factor
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ABSTRACT: Rational development of novel therapeutic strategies for alcoholism requires understanding of its underlying neurobiology and pathophysiology. Obtaining this knowledge largely relies on animal studies. Thus, choosing the appropriate animal model is one of the most critical steps in pre-clinical medication development. Among the range of animal models that have been used to investigate excessive alcohol consumption in rodents, the postdependent model stands out. It was specifically developed to test the role of negative affect as a key driving force in a perpetuating addiction cycle for alcoholism. Here, we will describe our approach to make rats dependent via chronic intermittent exposure to alcohol, discuss the validity of this model, and compare it with other commonly used animal models of alcoholism. We will summarize evidence that postdependent rats fulfill several criteria of a ‘Diagnostic and Statistical Manual of Mental Disorders IV/V-like’ diagnostic system. Importantly, these animals show long-lasting excessive consumption of and increased motivation for alcohol, and evidence for loss of control over alcohol intake. Our conclusion that postdependent rats are an excellent model for medication development for alcoholism is underscored by a summary of more than two dozen pharmacological tests aimed at reversing these abnormal alcohol responses. We will end with open questions on the use of this model. In the tradition of the Sanchis-Segura and Spanagel review, we provide comic strips that illustrate the postdependent procedure and relevant phenotypes in this review.Addiction Biology 12/2014; 20(1). DOI:10.1111/adb.12187 · 5.93 Impact Factor