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Gambling disorder is a growing societal concern, as recognized by its recent classification as an addictive disorder in the DSM-5. Case reports have shown that disulfiram reduces gambling-related behavior in humans. The purpose of the present study was to determine whether disulfiram affects performance on a rat gambling task, a rodent version of the Iowa gambling task in humans, and whether any changes were associated with alterations in dopamine and/or norepinephrine levels. Rats were administered disulfiram prior to testing on the rat gambling task or prior to analysis of dopamine or norepinephrine levels in brain homogenates. Rats in the behavioral task were divided into two subgroups (optimal vs suboptimal) based on their baseline levels of performance in the rat gambling task. Rats in the optimal group chose the advantageous strategy more, and rats in the suboptimal group (a parallel to problem gambling) chose the disadvantageous strategy more. Rats were not divided into optimal or suboptimal groups prior to neurochemical analysis. Disulfiram administered 2 h, but not 30 min, before the task dose-dependently improved choice behavior in the rats with an initial disadvantageous “gambling-like” strategy, while having no effect on the rats employing an advantageous strategy. The behavioral effects of disulfiram were associated with increased striatal dopamine and decreased striatal norepinephrine. These findings suggest that combined actions on dopamine and norepinephrine may be a useful treatment for gambling disorders.

A promising pharmacotherapy for alcohol use disorders has been positive allosteric modulators (PAMs) of the γ-aminobutyric acid receptor B (GABAB R) since GABAB R PAMs reduce ethanol drinking and self-administration in rodents.The current studies investigated a novel, selective GABAB R PAM, ADX71441, in comparison to naltrexone in a protocol of ethanol binge-like drinking, drinking-in-the-dark (DID), and in a model of long-term, excessive drinking, intermittent access to ethanol (IA).Male C57BL/6 J mice were given doses of ADX71441 (3, 10, 30 mg/kg, p.o.) before the fourth test day of repeated DID access to 20 % ethanol. Another group of mice had a history of 4 weeks of IA before ADX71441 (3, 10, 17 mg/kg, p.o.) treatment. The opioid antagonist, naltrexone (0.1, 1, 10 mg/kg, i.p.), was administered to different groups of mice in both protocols as a positive control.In both DID and IA protocols, ADX71441 showed a selective and potent reduction of ethanol drinking, but not water drinking, while naltrexone had a more modest and transient effect on reducing ethanol drinking. The long-lasting effect of ADX71441 agrees with its plasma pharmacokinetics in showing peak concentrations at 2 h followed by a slow decay lasting well beyond 8 h.These findings support previous studies demonstrating that GABAB R PAMs decrease voluntary ethanol intake without altering water intake. ADX71441 may be a worthwhile candidate for developing a treatment of alcoholism, yet its site of action in the brain and long-term pharmacological effects require further exploration.

We previously demonstrated that short-term treatment with a standardized kudzu extract (NPI-031) reduced alcohol drinking by men and women in a natural setting. The present study was conducted in nontreatment-seeking heavy drinkers to assess the safety and efficacy of 4 weeks of kudzu extract in an outpatient setting. This randomized between-subject, double-blind, placebo-controlled study involved 2 weeks of baseline, 4 weeks of treatment, and 2 weeks of follow-up. Seventeen men (21–33 years) who reported drinking 27.6 ± 6.5 drinks/week with a diagnosis of alcohol abuse/dependence took either kudzu extract (250 mg isoflavones, t.i.d.) or matched placebo on a daily basis. They reported alcohol consumption and desire to use alcohol using a wrist actigraphy device; twice weekly laboratory visits were scheduled to monitor medication adherence and adverse events. Medication adherence was excellent and there were no adverse events and changes in vital signs, blood chemistry, and renal or liver function. There was no effect on alcohol craving, but kudzu extract significantly reduced the number of drinks consumed each week by 34–57 %, reduced the number of heavy drinking days, and significantly increased the percent of days abstinent and the number of consecutive days of abstinence. A standardized formulation of kudzu extract produced minimal side effects, was well-tolerated, and resulted in a modest reduction in alcohol consumption in young nontreatment-seeking heavy drinkers. Additional studies using treatment-seeking alcohol-dependent persons will be necessary to determine the usefulness of this herbal preparation in reducing alcohol use in other populations.

Two pharmacotherapies are approved for treating alcohol craving (acamprosate and naltrexone), but both have shown mixed findings in animals and humans.The present experiments utilized a "reinforcer blocking" approach (i.e., rats were able to consume ethanol during treatment) to better understand the efficacy of these treatments for ethanol seeking and drinking using ethanol-dependent and nondependent rats.In "nondependent" experiments, drugs (acamprosate 50, 100, and 200 mg/kg; naltrexone 0.1, 0.3, and 1.0 mg/kg) were administered over 3-week periods prior to operant sessions with a low response requirement to gain access to reinforcers for 20 min. For "dependent" experiments, rats were made dependent in vapor/inhalation chambers.Acamprosate and naltrexone had similar effects on intake in nondependent and dependent rats; neither drug was selective for ethanol over sucrose drinking. In nondependent animals, naltrexone was more efficacious at more doses than acamprosate, and acamprosate's effects were limited to a dose that also had adverse effects on body weight. Both pharmacotherapies showed more selectivity when examining reinforcer seeking. In nondependent rats, acamprosate and naltrexone had response-attenuating effects in ethanol, but not sucrose, groups. In dependent animals, acamprosate had selective effects limited to a decrease in sucrose seeking. Naltrexone, however, selectively decreased ethanol-seeking in nondependent rats.The naltrexone-induced decreases in seeking suggested a change in incentive motivation which was selective for ethanol in nondependent rats. The "nondependent" paradigm may model early stages of "problem drinking" in humans, and the findings suggest that naltrexone could be a good intervention for this level of alcohol abuse and relapse prevention.

Acamprosate (calcium acetylhomotaurinate) is a glutamatergic neuromodulator used for the treatment of alcoholism, but its potential efficacy in the treatment of psychostimulant addiction has not been explored.The purpose of this study was to assess the effects of acamprosate on cocaine-stimulated locomotor activity, cocaine self-administration, and cue- and cocaine-induced reinstatement of cocaine-seeking behavior.All experiments utilized once-daily treatment for 5 consecutive days. First, the effects of saline or acamprosate (100, 300, or 500 mg/kg intraperitoneally) on body weight were examined. On the last day of treatment, locomotor activity was assessed before and after drug treatment, after which all animals received an acute challenge of cocaine (10 mg/kg). Next, a separate group of rats were trained to intravenously (IV) self-administer cocaine (0.6 mg/kg per infusion), subjected to extinction procedures, and then tested for effects of acamprosate on cue- or cocaine-induced reinstatement. A third group of rats was trained to self-administer cocaine as described above and were treated with saline or acamprosate before daily IV self-administration sessions.Repeated administration of 500 mg/kg acamprosate but not lower doses produced reductions in both body weight and spontaneous locomotor activity, and thus this dose was not tested further. Acamprosate at 300 mg/kg but not 100 mg/kg attenuated both cocaine- and cue-induced reinstatement without altering baseline patterns of cocaine self-administration or cocaine-stimulated hyperlocomotion.Acamprosate attenuates both drug- and cue-induced reinstatement of cocaine-seeking behavior, suggesting that this compound may serve as a potential treatment for preventing relapse in cocaine-addicted humans.

Rationale: Drugs that reduce relapse in alcoholics are thought to inhibit either positive reinforcement for drinking (e.g. naltrexone) or negative reinforcement (e.g. acamprosate), and may reduce the impact of conditioned stimuli associated with previous alcohol use. We have developed a model for such conditioning by repeatedly pairing ethanol administration with plus-maze exposure. Substitution of saline for ethanol greatly increased stretched-attend postures and time in the central square, conditioned to the environment. Objective: To test the hypothesis that if this behaviour indicates a negative affective state caused by the expectation of ethanol, it should be inhibited by drugs that reduce negative, but not positive, reinforcement. Methods: The effects of naltrexone and acamprosate on alcohol-conditioned abstinence behaviour were compared. Results: Acute administration of either drug alone produced no significant effects on plus-maze behaviour in naive mice. Naltrexone had no significant effect on the alcohol-conditioned abstinence behaviour, but acamprosate reduced the incidence of stretched-attend postures. Conclusions: The experiments replicated previous findings for alcohol/environment conditioned behaviour, and demonstrated, as predicted, that this was decreased by acamprosate but not by naltrexone. Effects of acamprosate on conditioned negative reinforcement may be the cause of this effect, but more work is required to establish the usefulness of this model in evaluation of anti-relapse drugs.

Four experiments examined the effect of naloxone pretreatment on the expression and extinction of ethanol-induced conditioned place preference (experiments 1, 2, 4) or conditioned place aversion (experiments 1, 3). DBA/2 J mice received four pairings of a distinctive tactile (floor) stimulus (CS) with injection of ethanol (2 g/kg) given either immediately before or after 5-min exposure to the CS. A different stimulus was paired with injection of saline. Pre-CS injection of ethanol produced conditioned place preference, whereas post-CS injection of ethanol produced conditioned place aversion. Both behaviors extinguished partially during repeated choice testing after vehicle injection. Naloxone (10 mg/kg) had little effect on the initial expression of conditioned place preference, but facilitated its extinction. Moreover, repeated naloxone testing resulted in the expression of a weak conditioned place aversion to the CS that initially elicited a place preference. In contrast, naloxone (1.5 or 10 mg/kg) enhanced expression of conditioned place aversion, thereby increasing its resistance to extinction. A control experiment (experiment 4) indicated that repeated testing with a different aversive drug, lithium chloride, did not affect rate of extinction or produce an aversion to the CS previously paired with ethanol. These findings do not support the suggestion that naloxone facilitates the general processes that underlie extinction of associative learning. Also, these data are not readily explained by the conditioning of place aversion at the time of testing. Rather, naloxone's effects appear to reflect a selective influence on maintenance of ethanol's conditioned rewarding effect, an effect that may be mediated by release of endogenous opioids. Overall, these findings encourage further consideration of the use of opiate antagonists in the treatment of alcoholism.

These experiments evaluated the ability of naltrexone (NTX) to reduce selectively oral and i.v. ethanol-reinforced responding, and examined the ethanol-NTX interaction in terms of the competitive opioid antagonist property of NTX. Five rhesus monkeys self-administered ethanol or sucrose and concurrently available water. Ethanol concentration was varied from 0.25% to 8% (w/v). Naltrexone (0.032-0.32 mg/kg) or saline was given i.m. 30 min prior to some drinking sessions. NTX (0.32 mg/kg) reduced ethanol-reinforced responding at the concentration that maintained the most responding (1% or 2%). NTX (0.1 mg/kg) reduced ethanol-reinforced responding, both at a low ethanol concentration (0.25%) that produced little ethanol intake (g/kg), and at a higher concentration (4%) with an appreciable intake. Thus, NTX (0.1 mg/kg) shifted the ethanol concentration-consumption curve down, in an insurmountable manner. NTX (0.1 and 0.32 mg/kg) also reduced reinforced responding for sucrose 100 g/l. In another experiment, three rhesus monkeys were given opportunities to self-administer ethanol i.v. NTX (0.1 mg/kg) reduced the number of ethanol injections obtained by the monkeys at all ethanol doses tested (0.01, 0.032, and 0.1 g/kg per injection). The dose-effect curve was also shifted down. These results showed that NTX reduced behavior maintained by either ethanol or sucrose non-selectively. Furthermore, the ability of NTX to suppress ethanol-reinforced responding did not depend on the route of ethanol administration and was not overcome by increasing the concentration or dose per injection of ethanol.

In humans, the retrieval of memories associated with an alcohol-related experience frequently evokes alcohol-seeking behaviour. The reconsolidation hypothesis states that a consolidated memory could again become labile and susceptible to disruption after memory retrieval. The aim of our study was to examine whether retrieval of alcohol-related memories undergoes a reconsolidation process. For this purpose, male Wistar rats were trained to self-administer ethanol in the presence of specific conditioned stimuli. Thereafter, animals were left undisturbed in their home cages for the following 21 days. Memory retrieval was performed in a single 5-min exposure to all alcohol-associated stimuli. The protein synthesis inhibitor anisomycin, the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 and acamprosate, a clinically used drug known to reduce a hyper-glutamatergic state, were given immediately after retrieval of alcohol-related memories. The impact of drug treatment on cue-induced alcohol-seeking behaviour was measured on the following day and 7 days later. Administration of both anisomycin and MK-801 reduced cue-induced alcohol-seeking behaviour, showing that memory reconsolidation was disrupted by these compounds. However, acamprosate had no effect on the reconsolidation process, suggesting that this process is not dependent on a hyper-glutamatergic state but is more related to protein synthesis and NMDA receptor activity. Pharmacological disruption of reconsolidation of alcohol-associated memories can be achieved by the use of NMDA antagonists and protein synthesis inhibitors and may thus provide a potential new therapeutic strategy for the prevention of relapse in alcohol addiction.

Acamprosate is a widely utilized, efficacious treatment for relapse prevention in alcohol-dependent patients; yet, little is known regarding its therapeutic mechanism of action. The aim of the present study was to examine the effect of acamprosate on cue reactivity and alcohol priming in alcohol-dependent patients. In a double-blind design, 56 treatment seeking patients were randomized to 21 days of either acamprosate or placebo treatment and then participated in a series of cue- and alcohol-priming sessions. Alcohol cues consisted of a mixture of alcohol related visual, tactile, olfactory, and auditory stimuli. Non-alcohol-related cues were contextually similar but had no connection to alcohol. In the alcohol-priming procedure, patients were provided with an alcohol drink of their own choice at a dose corresponding to 0.20 gr. EtOH/kg bodyweight. Subjective, physiological, and biological measurements were recorded before and after each test session. Following study completion, all patients were referred to formal treatment. The results showed that acamprosate attenuated the subjective craving induced by alcohol priming in comparison to placebo-treated patients. Furthermore, acamprosate reduced alcohol-induced elevation in blood-cortisol levels. Lastly, there was a negative correlation between acamprosate plasma levels and alcohol craving following a priming drink. No effects of acamprosate on cue reactivity, or on the acute rewarding and sedating effects of the priming drink, were observed. These results suggest a potential mechanism by which acamprosate mediates its therapeutic effect in the treatment of alcoholism, by attenuating the urge to drink following an alcohol slip.

Rationale: In spite of many recent studies on the effects of acetaldehyde, it is still unclear whether acetaldehyde mediates the reinforcing and/or aversive effects of ethanol. Objectives: The present study reexamined the role of acetaldehyde in ethanol-induced conditioned taste aversion (CTA). A first experiment compared ethanol- and acetaldehyde-induced CTA. In a second experiment, cyanamide, an aldehyde dehydrogenase inhibitor, was administered before conditioning with either ethanol or acetaldehyde to investigate the effects of acetaldehyde accumulation. Methods: A classic CTA protocol was used to associate the taste of a saccharin solution with either ethanol or acetaldehyde injections. In experiment 1, saccharin consumption was followed by injections of either ethanol (0, 0.5, 1.0, 1.5 or 2.0 g/kg) or acetaldehyde (0, 100, 170 or 300 mg/kg). In experiment 2, the rats were pretreated with either saline or cyanamide (25 mg/kg) before conditioning with either ethanol or acetaldehyde. Results: Both ethanol and acetaldehyde induced significant CTA. However, ethanol produced a very strong CTA relative to acetaldehyde that induced only a weak CTA even at toxic doses. Cyanamide pretreatments significantly potentiated ethanol- but not acetaldehyde-induced CTA. Conclusions: The present results indicate that ethanol-induced CTA does not result from brain acetaldehyde effects. In contrast, it is suggested that the reinforcing effects of brain acetaldehyde might actually reduce ethanol-induced CTA. Our results also suggest that the inhibition of brain catalase activity may contribute to the potentiating effects of cyanamide on ethanol-induced CTA.

Preclinical studies have exploded our knowledge about the behavioral and biological underpinnings of alcoholism. These studies suggest that certain neurotransmitters, particularly those interacting with the opioid, N-methyl-d-aspartate, and monoamine systems, may play a critical role in the expression of alcohol-drinking and other behaviors associated with its abuse liability. Built upon this foundation, important advances have been made in the development of therapeutic medications for the treatment of alcoholism. Of the medications reviewed, acamprosate’s potential appears to be the most widely established. In the USA, naltrexone was approved by the Food and Drug Administration in 1995 for the treatment of alcoholism; however, the results of some studies have been less encouraging. Naltrexone’s reliance on high compliance rates for efficacy may, eventually, limit its potential in clinical settings offering generic treatment for alcoholism. The relative paucity of dose-response studies on naltrexone’s effects in treating alcoholics is an important gap in the literature. Recent data from a large clinical trial suggests that ondansetron, a serotonin3 antagonist, offers new hope for the treatment of early onset alcoholics; a type of alcoholism most difficult to manage with psychosocial measures alone. Different subtypes of alcoholic may, therefore, have varying treatment responses to serotonergic agents. Matching subtypes of alcoholic to effective treatment medications based upon their different biologies remains an important therapeutic goal. Combinations of effective pharmacological agents need exploration as they may prove to be synergistic, and could shepherd in a new era of treatments aimed at multiple neurotransmitter targets associated with the alcoholism disease. The coming decade promises more powerful tools for characterizing drug effects on alcohol drinking, thereby closing the gap between animal models of addiction and the human condition.

Rationale: Given that alcoholics drink for different reasons, it is not likely that a single pharmacotherapeutic agent will be equally effective for all alcoholics. Hence, the development of new pharmacotherapeutic agents that are capable of reducing alcohol intake remains an important focus in the field of alcohol research. Objective: The objective of the present study was to examine the effects of the δ2 receptor antagonist naltriben (0.60–4.0 mg/kg) on operant responding maintained by the presentation of ethanol (EtOH) or saccharin in alcohol-preferring (P) rats. Methods: P rats were trained under a concurrent schedule [fixed ratio (FR)4–FR4] to press one lever for EtOH (10% v/v) and another for saccharin (0.0125–0.05% w/v) during a 60-min session. Naloxone, a non-specific opioid receptor antagonist, served as a reference antagonist. Results: When responding maintained by EtOH and saccharin were equated under baseline conditions, naloxone (0.003125–0.75 mg/kg) reduced levels of EtOH-maintained responding by 46–82%. None of the naloxone doses significantly reduced responding maintained by saccharin. Naltriben (0.9–4.0 mg/kg) reduced EtOH-maintained responding by 44–76%, while saccharin-maintained responding was reduced only by the highest dose of naltriben (4.0 mg/kg). Analysis of the EtOH within-session response pattern revealed that naloxone suppressed EtOH-maintained responding during the entire operant session and led to early termination of responding. Low doses of naltriben (0.90 mg/kg and 1.2 mg/kg) suppressed responding during the latter portion of the operant session, while higher doses (2.0, 3.0, 4.0 mg/kg) decreased responding during the entire session and led to early termination of responding. Conclusions: The results of the present study strengthen previous reports from our laboratory suggesting that naltriben, the selective δ2 opioid receptor antagonist, suppresses EtOH self-administration in rats selectively bred for high EtOH consumption. The results also suggest that naltriben may be a potential candidate for use as a pharmacotherapeutic agent in the treatment of EtOH dependence.

Naltrexone (NTX) has been shown to be efficacious for the treatment of alcohol dependence. Since alcohol and cocaine use disorders commonly co-occur, we conducted a randomized, double-blind, placebo-controlled trial of NTX 50 mg/day in 64 subjects with comorbid alcohol and cocaine use disorders. Although subjects in both groups reduced their consumption of both alcohol and cocaine during the 8-week trial, there was no consistent advantage to NTX over placebo treatment. We conclude that, due to behavioral, neurochemical, or other factors, individuals with both alcohol and cocaine use disorders are distinct from those dependent on alcohol alone, and that NTX at a dosage of 50 mg/day is not efficacious in this patient population. Several factors, including medication dosage, length of treatment, sample size and attrition rate, limit the interpretation of these findings. Consequently, we recommend that subsequent trials of NTX to reduce the risk of relapse in patients with comorbid alcohol and cocaine use disorders take these issues into account.

Over the past decade, research on medications to treat alcohol problem has flourished. Naltrexone and acamprosate are tangible fruits of such endeavors and each has now earned approval in a large number of countries. Recent studies on naltrexone indicate that patient compliance is important if full benefits are to be achieved. Several laboratory studies with human subjects are beginning to elucidate the mechanisms underlying efficacy of naltrexone, as well as explaining variability of response among subpopulations of drinkers. In addition to these two agents, recent investigations have also demonstrated that the antidepressants desipramine, imipramine, and fluoxetine reduce mood-related symptoms and, to some extent, drinking itself in alcoholics who are depressed. Research to date suggests that opioid antagonists and selective serotonin reuptake inhibitors are more effective in reducing alcohol intake when used in combination. Clinical issues, methodology, and directions for future research are also reviewed in this article. In particular, issues addressed include alternative dosage regimens, necessary duration of treatment, employment of medications in combination, integration of pharmacologic agents with behavioral interventions, enhancement of patient compliance, and concurrent treatment of psychiatric comorbidity.

The time course of the benzodiazepine (BDZ) inverse agonist RO19-4603 in antagonizing ethanol (EtOH) intake was investigated in alcohol-preferring (P) rats (n=7) maintained on 24-h continuous free-choice access to EtOH (10% v/v), water, and food. After fluid intakes had stabilized over several weeks, animals were injected with Tween-80 vehicle solution or RO19-4603 (0.075, 0.150, and 0.30 mg/kg). EtOH and water intakes were determined at 8- and 24-h intervals. RO19-4603 caused a marked attenuation of EtOH drinking with each of the doses tested. EtOH intake during the 8-h following 0.075, 0.150, and 0.30 mg/kg RO19-4603 was decreased by approximately 36, 74, and 57%, respectively. Intakes during the 24-h interval were similar to the vehicle control condition. However, 32 h post-drug administration, EtOH intakes were reduced to approximately 27, 31, and 29% following the 0.075, 0.150 and 0.30 mg/kg doses, respectively. To further confirm the reliability of the RO19-4603 dose-response effect, and its selectivity for EtOH, the highest dose condition (0.30 mg/kg) was tested twice. The second 0.30 mg/kg dose condition exerted a profile of effects similar to the initial treatment; 8 h following administration, intake was decreased to 60% of the control level, and 32 h post-drug administration intake was decreased to approximately 46% of the controls. These decreases were evidently selective in comparison with water, since water drinking showed compensatory increases which paralleled the decreased EtOH consumption. Dose-response comparisons indicated that 0.150 mg/kg approaches the maximum effective dose, since the 0.30 mg/kg dose of RO19-4603 did not produce an additional decrease in EtOH intake. Furthermore, unlike the lower doses, the 0.30 mg/kg dose failed to yield reliable compensatory increases in water drinking. The results demonstrated that a single acute administration of RO19-4603 produces prolonged and selective suppression of EtOH intake in P rats maintained on 24-h continuous free access to EtOH. While it is not clear at present what properties of the ligand might explain the observed effects on EtOH intake, these findings along with our previous work, clearly suggest that RO19-4603 may modify neuronal processes that promote EtOH self-administration. Neural transmission at the GABAA-BDZ receptor complex may play an important role in mediating EtOH reinforcement.