The development of acamprosate as a treatment against alcohol relapse

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.

Keywords: acamprosate; alcoholism; calcium; craving; glutamate; relapse.

Figure 1

Chemical structures for acamprosate (N-acetyl-homotaurine), taurine, GABA and glutamate.

Figure 2. Elements of the two-bottle choice paradigm

(A) In order to induce a preference for alcohol or overt withdrawal symptoms, several early experiments included an initiation phase where rats were housed for approximately one week with 10 – 20% (w/v) alcohol (EtOH) as the sole drinking solution. Due to complications in maintaining normal body mass in the subjects, this practice is less common in current experiments. (B) In the standard two-bottle choice test, rats are housed with two drinking bottles, where one contains ordinary water and the other contains 10 – 20% (w/v) alcohol dissolved in tap water. The presentation of the solutions is alternated between the left and right bottles on a regular basis to avoid the development of side-bias. (C) Several experiments introduce alternative alcohol solutions with additional drinking bottles to measure the evolution of the rat’s preference for alcohol.

Figure 3. The alcohol deprivation effect (ADE) paradigm

(A) In a typical ADE experiment, rats are given access to both an alcohol (10 – 20%, w/v) solution and ordinary water in separate drinking bottles in their home cages over a span of several weeks. (B) After the establishment of regular daily consumption of the alcohol solution (which may only occur in a subset of rats, particularly if they are not bred to be alcohol-preferring), the alcohol solution is replaced with another ordinary water bottle for several (3 to 7 or more) days. (C) The alcohol solution is returned for one or more days of assessment. The side of the alcohol bottle is randomly determined and alternated between days in multiday tests. An increase in alcohol consumption relative to the pre-abstinence baseline is reported as evidence of ADE.

Figure 4. Self-administration apparatus with cues and controlled delivery of alcohol reinforcers

In a typical operant conditioning chamber for the self-administration training, the front panel is equipped with two retractable levers (A, B). One lever is determined to be the active lever, where responding is reinforced with delivery of alcohol, and the other lever usually results in no programmed consequences. Above each lever is a stimulus light (C, D) that temporarily illuminates upon the successful schedule completion of the operant task, usually a single response on the active lever, producing a conditioned stimulus (CS+). The active and inactive levers may be alternated between sessions or groups of subjects. Alcohol is delivered in from a computer-controlled syringe pump into a receptacle installed in the rear wall (E). Sessions where alcohol reinforcement is available may be signaled by olfactory stimuli (S+) provided by drops baking extract in the bedding below the floor bars (F). An alternative odor would be used in sessions where schedule completions result in delivery of water or no reinforcement (S−). The chamber is also equipped with a tone generator that can be activated to signal a successful schedule completion in these sessions (CS−). Chambers are frequently equipped with a house light (G) and white noise generator (H) to provide additional means to generate discriminative cues (S+/CS+ and S−/CS−) during training and testing.

Figure 5. Schematic of the extinction/reinstatement model using discriminative cues

(A) Self-administration training is initiated by a multi-week procedure where the rat is trained to respond on the active lever for delivery of a sweetened solution (sucrose or saccharin), which is gradually replaced by alcohol (8-10%, w/v) dissolved in tap water. (B) Alcohol self-administration training continues in the same operant chamber, but two reinforcement contingencies are used in separate daily sessions. In the alcohol reinforcement condition, signaled by the combination of ambient and lever-contingent cues (S+/CS+), responses on the active lever are reinforced with delivery of the alcohol solution. In the control condition signaled by a distinct set of cues (S−/CS−), responses on the active lever result in delivery of water or no programmed consequences. (C) Following the establishment of stable self-administration behavior, rats undergo extinction training in the same chambers, where responding on either lever results in no delivery of reinforcement or presentation of cues. Extinction training continues in daily sessions until rats no longer respond on either lever above a low (20% of baseline self-administration levels) criterion. (D) In test sessions for reinstatement of alcohol-seeking behavior elicited by S+ cues, active lever responses result in presentation of the lever-contingent cues (CS+), but not alcohol reinforcement. These tests alternate with S−/CS− sessions to establish the specificity of reinstated operant behavior.