Naltrexone aversion and treatment efficacy are greatest in humans and rats that actively consume high levels of alcohol

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Abstract

The opioid antagonist naltrexone is the standard pharmacotherapy for alcoholism, although compliance is often low. The mechanism by which naltrexone reduces drinking is yet unclear. Here we show that in active alcoholics the magnitude of naltrexone treatment efficacy is correlated with the level of naltrexone-induced aversive side effects. This correlation is not observed when subjects are sober, but emerges following alcohol administration, when subjects are intoxicated. In contrast, there is no correlation following placebo administration. To clarify these results, naltrexone was administered to ethanol-consuming rats prior to quantification of naltrexone aversion. Ethanol consumption preceding naltrexone treatment was again correlated with subsequent naltrexone-induced aversion, and this aversion correlated with subsequent decrease in ethanol consumption. In contrast, when naltrexone was given to ethanol-free rats, aversion was not predictive of ethanol consumption. We conclude that naltrexone treatment efficacy is greater during active ethanol consumption and may be partly due to aversive side effects.

Introduction

Although FDA approved for over a decade, naltrexone (Revia) has failed to gain widespread acceptance as a treatment for alcohol abuse. Doctors hesitate to prescribe naltrexone because of perceived ineffectiveness, expense, and unpleasant side effects (Mark et al., 2003), and because of low patient compliance (Kranzler et al., 2000, Bouza et al., 2004). Despite these limitations, naltrexone is an effective treatment for alcohol abuse. It reduces the number of heavy drinking days (Monti et al., 2001, Balldin et al., 2003, Gueorguieva et al., 2007; Rosner et al., 2008), craving for alcohol (Davidson et al., 1999, Chick et al., 2000), and may inhibit relapse to drinking (Anton et al., 1999, Guardia et al., 2002, Latt et al., 2002). Therefore, the fact that its use may be limited by aversive side effects suggests that further investigation into the relationship between naltrexone-induced side effects and treatment efficacy could lead to improved therapy for alcoholism.

The ventral tegmental area (VTA) is a brain region crucial to the rewarding effects of ethanol. Alcohol preferring rats will self-administer ethanol directly into the VTA (McBride et al., 1993), while the microinjection of dopamine D2 antagonists decreases ethanol consumption (Nowak et al., 2000). Furthermore, opioids can produce conditioned place preference when microinjected into the VTA (Bals-Kubik et al., 1993, Olmstead and Franklin, 1997, Terashvili et al., 2004) and an opioid action in the VTA contributes to expression of ethanol place preference in mice (Bechtholt and Cunningham, 2005). In human alcoholics, the VTA is activated following exposure to alcohol related olfactory cues (Kareken et al., 2004) suggesting an involvement of this area in the motivation to consume ethanol. By injecting naltrexone into the VTA of ethanol consuming rats, it is possible to study whether naltrexone efficacy and aversion share a common neural substrate.

Alcoholics vary in their level of ethanol consumption upon entry into treatment, making it challenging to determine how recent experience with ethanol contributes to naltrexone effectiveness (Killeen et al., 2004). Place conditioning provides a way to address this issue in animals. The benefit of using a place conditioning paradigm with rats is that alcohol exposure can be tightly controlled and examined in relation to naltrexone administration. These results can then be compared to those obtained in human alcoholics undergoing naltrexone treatment.

There is evidence that ethanol consumption leads to the release of an endogenous opioid, which promotes further ethanol consumption (Reid and Hunter, 1984, Nylander et al., 1994, Marinelli et al., 2005). Since naltrexone blocks opioid receptors, it likely reduces ethanol consumption by blocking the action of this endogenously released opioid. However, when given after even brief exposure to exogenous opioids, opioid antagonists produce robust aversive effects in humans (Heishman et al., 1989) and rats (Kim et al., 1990). If ethanol consumption does lead to endogenous opioid release, then naltrexone-induced aversion should be correlated with ethanol consumption. Furthermore, if the unpleasant side effects of naltrexone are linked to treatment efficacy, there should also be a correlation between naltrexone-induced aversion and subsequent reduction of ethanol administration.

Section snippets

Subjects

Subjects (n = 30) were recruited via an online flyer indicating solicitation of heavy social drinkers for a paid study of the effects of naltrexone on drinking. All subjects were between 21 and 40 years of age and were screened for neurological disease, psychoactive medications, current treatment for other psychological disorders, and addiction to substances other than alcohol. Subjects also received a physical examination prior to participation and had blood drawn to check cell counts and to

Human data

Subjects scored an average of 25.8 ± .6 on the DUSI, Domain IB, 9.96 ± .83 on the AUDIT, and 10.0 ± .3 on the KMSK, Alcohol Domain. Pre-study drinking, as indicated during the screening visit, was 13.0 ± .9 drinks per week for all subjects. Riboflavin data indicate that subjects were 100% compliant for both naltrexone and placebo administration, and all subjects verbally acknowledged taking all study medication. Additionally, all subjects turned in a complete set of alcohol use diaries.

Subjects

Discussion

Our data demonstrate that the magnitude of naltrexone-induced aversion is positively correlated with the amount of ethanol that humans and rats have consumed during naltrexone treatment. Additionally, in both humans and rats, the level of this naltrexone-induced aversion predicts subsequent reduction in ethanol consumption. We also show that the correlation between naltrexone aversion and ethanol consumption is absent in rats under conditions in which ethanol is either not present or is

Acknowledgments

This work was supported by the Wheeler Center for the Neurobiology of Addiction, the Ernest Gallo Clinic and Research Center, and by California State Funds. The experiments contained herein comply with the current laws of the United States and were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (NIH).

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