Dopamine and Alcohol Dependence: From Bench to Clinic

Alcohol dependence, a chronic relapsing psychiatric disorder, is a major cause of mortality and morbidity. The role of dopamine in alcohol‐induced reward as well in the development of alcohol dependence is reviewed herein. Both preclinical and clinical studies have suggested that alcohol activates the mesolimbic dopamine system (defined as a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens (NAc, i.e. ventral striatum)) leading to a euphoric sensation. Alcohol dependence is characterized by a disruption in the reward‐related brain areas including fewer dopamine D2 receptors in ventral striatum. Investigations of the underlying dopaminergic mechanisms involved during the development and maintenance of alcohol dependence could identify novel targets. Human and rodent experimental studies show that dopamine receptor antagonists, agonists and partial agonists as well as dopamine stabilizers influencing dopamine transmission, alter alcohol‐mediated behaviours and thus may be potential treatment targets for alcohol dependence. Although there exists promising preclinical results, the majority of placebo‐controlled randomized clinical trials with traditional dopamine antagonists and agonists have so far have been discouraging. Furthermore, the severe side-effect profiles of many of these compounds may limit their clinical use. Newer dopamine agents, such as partial agonists and dopamine stabilizers, attenuate alcohol‐mediated behaviours in rodents as well as humans. Preclinical as well as clinical studies have shown that substances indirectly targeting the mesolimbic dopamine system may be potential targets for attenuation of alcohol reward. Collectively, the data reviewed herein may contribute to further understanding the complex mechanisms involved in development of alcohol dependence and we suggest that the newer dopamine agents as well as indirect modulators of dopamine signalling deserve to be further evaluated for treatment of alcohol dependence

Alcohol Dependence Associated with Increased Utilitarian Moral Judgment: A Case Control Study

Recent studies indicate that emotional processes, mediated by the ventromedial prefrontal cortex (VMPC), are of great importance for moral judgment. Neurological patients with VMPC dysfunction have been shown to generate increased utilitarian moral judgments, i.e. are more likely to endorse emotionally aversive actions in order to maximize aggregate welfare, when faced with emotionally salient personal moral dilemmas. Patients with alcohol dependence (AD) also exhibit impairments in functions mediated by the prefrontal cortex, but whether they exhibit increased utilitarian moral reasoning has not previously been investigated. The aim of this study was to investigate moral judgment in AD patients (n = 20) compared to healthy controls (n = 20) matched by sex, age and education years. Each subject responded to a battery of 50 hypothetical dilemmas categorized as non-moral, moral impersonal and moral personal. They also responded to a questionnaire evaluating explicit knowledge of social and moral norms. Results confirmed our hypothesis that AD patients generated increased utilitarian moral judgment compared to controls when faced with moral personal dilemmas. Crucially, there was no difference in their responses to non-moral or impersonal moral dilemmas, nor knowledge of explicit social and moral norms. One possible explanation is that damage to the VMPC, caused by long term repeated exposure to alcohol results in emotional dysfunction, predisposing to utilitarian moral judgment. This work elucidates a novel aspect of the neuropsychological profile of AD patients, namely a tendency to generate utilitarian moral judgment when faced with emotionally salient moral personal dilemmas

Mortality in adult children of parents with alcohol use disorder: a nationwide register study

Research suggests that adult children of parents with harmful alcohol use are at increased risk for premature death. This national cohort study investigated mortality in adult children of parents with alcohol use disorder (AUD), adjusting for sociodemographic variables. The study used 1973 to 2018 data from Swedish national registers to compare mortality risk in children who had >= 1 parent with AUD (ICD-10 code F10 and its ICD-8 and ICD-9 equivalents) (n = 122,947) and those who did not (n = 2,298,532). A Cox regression model adjusted for year of birth, sex, parental education, and childhood loss of a parent was used. Before the age of 18 years, about 5% of children born in Sweden lived with >= 1 parent who had a clinical diagnosis of AUD. Overall mortality was higher in adult children of parents with AUD: hazard ratio (HR) 1.76, 95% confidence interval (CI) 1.71-1.82. Mortality remained elevated after adjustments for sociodemographic factors (HR 1.45, 95% CI 1.40-1.50). Children of parents with AUD had increased mortality from all investigated causes. The highest excess risk was for death from drug-related causes (excluding accidental poisonings) (HR 3.08, 95% CI 2.74-3.46). For most causes, mortality was higher if the mother had AUD than if the father had AUD. Patterns of mortality were similar in both sexes. This study provides evidence that parental AUD raises the risk of offspring mortality from preventable causes such as drug use, suicide (HR 2.16, 95% CI 1.98-2.36), accident (HR 2.00, 95% CI 1.87-2.13), and assault (HR 1.76, 95% CI 1.38-2.24).</p

Evaluation of Naltrexone as a treatment for amphetamine dependence

Amphetamine addiction is a disease that affects millions of people worldwide and lacks effective treatment. An estimated 35 million persons are reported to abuse amphetamines, which is more than the total number of cocaine and heroin abusers combined. A majority of intravenous drug users in Sweden abuse amphetamine, pushing this disorder to the forefront of psychiatric problems. At present, there is no approved pharmacotherapy for amphetamine dependence. Several lines of evidence point towards involvement of the endogenous opioid system in the pathophysiology of stimulant addiction. The opioid antagonist naltrexone has shown to modulate some of the behavioral and neurochemical effects of amphetamine in animal models. The aim of this thesis was to investigate naltrexone in humans as a potential pharmacotherapy for the treatment of amphetamine dependence. In the first study, we examined the effect of an acute dose of naltrexone in drugnaïve individuals. Structured batteries of subjective, physiological and behavioral measures were systematically administered to investigate the interaction effect of naltrexone and amphetamine. The results demonstrated that pre-treatment with naltrexone significantly reduces the subjective effects of amphetamine. Pre-treatment with naltrexone had no effect on the physiological and behavioral measures. In the next study, we examined the effect of an acute dose of naltrexone on the subjective, physiological and biochemical effects of amphetamine in dependent individuals, using a double-blind placebo controlled design. Pre-treatment with naltrexone significantly attenuated the subjective effects of amphetamine. In addition, craving for amphetamine was blunted by naltrexone. This data provide the proof-ofconcept that naltrexone not only dampens the subjective effect of amphetamine in the event of drug use, but also decreases the likelihood of additional drug consumption Thereafter, we investigated the effect of chronic treatment with naltrexone in amphetamine dependent individuals, in an open-label design. The aim was to assess the tolerability and compliance to naltrexone in this new population. Twelve weeks of treatment with naltrexone led to a reduction in both frequency and quantity of drug consumption. Overall, the results showed that naltrexone was well tolerated with minimal side effects. Finally, we investigated naltrexone for the treatment of amphetamine dependence in a randomized placebo-controlled trial. Patients either received 12-weeks of treatment with naltrexone or placebo. Twice-weekly urine toxicology tests were performed and in addition patients received weekly relapse prevention therapy. The results indicate that treatment with naltrexone reduced the percentage of amphetaminepositive urine samples in patients with chronic amphetamine dependence. Continued treatment with naltrexone also led to a reduction in craving as compared to placebo. In addition, the medical safety of naltrexone was further confirmed in this population. In conclusion, naltrexone pharmacotherapy significantly reduces the reinforcing effects of amphetamine in acute and chronic dosing models. Taken together, this thesis provides support for the potential use of naltrexone as a treatment for amphetamine dependence

Alcohol Use Disorder Displays Trait-Related Reductions in Prosocial Decision Making

Background: Alcohol use disorder (AUD) is associated with deficits in social cognition, but the relationship between harmful alcohol use and the processes underlying interactive social behavior is still unknown. We hypothesized that prosocial decision making is reduced in AUD and that individual differences in the underlying processes are key to better understanding these reductions. Methods: In one laboratory study (Swedish participants, n = 240) and one confirmatory online study (American participants, n = 260), we compared young adults with AUD with age-, gender-, and education-matched healthy control subjects on 6 facets of prosocial decision making. We used standardized behavioral economic tasks, namely the dictator game, ultimatum game, trust game, and third-party game. To better understand the expected differences in prosociality, we evaluated attention by tracking eye gaze, decision response time, clinical symptoms, and social cognition. Results: Altruism (lab study: p = .007; online study: p < .001), fairness (lab study: p = .003; online study: p = .007), and reciprocal trust (lab study: p = .007; online study: p = .039) were reduced in individuals with AUD compared with healthy control subjects, whereas trust and third-party punishment and compensation were comparable in both studies. Reduced prosociality was associated with attending to the selfish response option, faster response time, and moral attitudes, while being dissociated from both psychiatric symptoms and drinking history in AUD. Conclusions: Individuals with AUD have trait-related reductions in prosocial decision making that do not vary with drinking history or psychiatric symptom load. These reductions were confined to one-to-one interactions accompanied by differences in attention, decision time, and moral attitudes

Impulsive choice in individuals with comorbid amphetamine use disorder and attention deficit-hyperactivity disorder

Abstract Background Amphetamine use disorder (AMPH) and attention deficit-hyperactivity disorder (ADHD) often co-occur and are associated with poor treatment outcomes. Elevated impulsivity is a core feature in both disorders. Little is known however about the specific neurocognitive profile regarding different facets of impulsivity, and specifically impulsive choice, in comorbid populations. Methods Three groups (ADHD + AMPH, ADHD only and healthy controls (HC)) were assessed with self-reported impulsivity and cognitive tasks of impulsive choice, operationalized as delay aversion (DA) and reflection impulsivity. Results Twenty-nine participants with comorbid ADHD + AMPH, 25 participants with ADHD only and 116 HC completed screening, including self-rating scales, and cognitive testing. 20, 16 and 114 participants completed computerized cognitive tasks in the ADHD + AMPH group, ADHD group and HC group, respectively. The ADHD + AMPH group reported significantly higher motor, attentional and non-planning impulsiveness, and showed a significantly higher degree of impulsive choice, compared to both groups. There were no differences in task-related impulsiveness between ADHD only and HC. Conclusions The current findings suggest that individuals with ADHD + AMPH have overall elevated levels of impulsivity compared to individuals with ADHD only. In addition, that ADHD + AMPH is specifically associated with impairments in task-related impulsive choice, which was not found in ADHD only compared to HC. The neurocognitive profile in this specific patient group may represent a need for more systematic screening within healthcare settings in order to develop effective and targeted treatment for comorbid patients. Trial registration EudraCT, 2012–004298-20

Methylphenidate for attention deficit hyperactivity disorder and drug relapse in criminal offenders with substance dependence : a 24-week randomized placebo-controlled trial.

AIM: To test the efficacy and safety of osmotic release oral system (OROS) methylphenidate (MPH) in doses up to 180 mg/day to treat attention deficit hyperactivity disorder (ADHD) and prevent any drug relapse in individuals with a co-diagnosis of ADHD and amphetamine dependence. DESIGN: Randomized placebo-controlled 24-week double-blind trial with parallel groups design. SETTING: Participants were recruited from medium security prisons in Sweden. The medication started within 2 weeks before release from prison and continued in out-patient care with twice-weekly visits, including once-weekly cognitive behavioural therapy. PARTICIPANTS: Fifty-four men with a mean age of 42 years, currently incarcerated, meeting DSM-IV criteria for ADHD and amphetamine dependence. MEASUREMENTS: Change in self-reported ADHD symptoms, relapse to any drug use (amphetamine and other drugs) measured by urine toxicology, retention to treatment, craving and time to relapse. FINDINGS: The MPH-treated group reduced their ADHD symptoms during the trial (P = 0.011) and had a significantly higher proportion of drug-negative urines compared with the placebo group (P = 0.047), including more amphetamine-negative urines (P = 0.019) and better retention to treatment (P = 0.032). CONCLUSIONS: Methylphenidate treatment reduces attention deficit hyperactivity disorder symptoms and the risk for relapse to substance use in criminal offenders with attention deficit hyperactivity disorder and substance dependence

Demographic and clinical data of the 39 subjects participating in the study, with values in parenthesis referring to 1 standard deviation.

<p> <i>1) MADRS  =  Montgomery-Asberg Depression Rating Scale 2) AUDIT  =  Alcohol Use Disorder Identification Test 3) DUDIT  =  Drug Use Disorder Identification Test.</i></p

Knowledge of explicit social and moral norms was evaluated using 15 items from the Moral Behaviour Scale [16], to which the subjects responded by choosing “not wrong”, “mildly wrong”, “moderately wrong” or “severely wrong”, on a 4-point rating scale.

<p>Knowledge of explicit social and moral norms was evaluated using 15 items from the Moral Behaviour Scale <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039882#pone.0039882-McGuire1" target="_blank">[16]</a>, to which the subjects responded by choosing “not wrong”, “mildly wrong”, “moderately wrong” or “severely wrong”, on a 4-point rating scale.</p