Dopamine and Alcohol Dependence: From Bench to Clinic

Olanzapine, another example of a second generation of antipsychotics, has been evaluated in a human cue‐craving study, where the compound reduced the urge to drink post‐exposure to alcohol cues, without affecting the rewarding effects of alcohol following the consumption of a priming dose of alcohol [152]. Based on this clinical finding and the knowledge that olanzapine also has a high affinity for the D4 receptors, it was hypothesized whether the dopamine receptor D4 gene maybe involved in meditating its clinical effects. These data are supported by the findings that olanzapine reduces craving for alcohol at baseline for both individuals with the DRD4 shorter and longer allele, but only reduces craving after exposure to alcohol cues and after a priming dose of alcohol for individuals with the DRD4 longer allele [166]. Overall, the results from studies evaluating olanzapine as a potential medication for alcohol dependence have provided evidence of a marginal effect restricted to a sub population of patients (with the longer dopamine D4 receptor allele).

It should, however, be noted that recent clinical trials in alcohol‐dependent individuals were unable to find a beneficial effect of varenicline based on self‐reported alcohol consumption [212, 213]. Besides glycine receptors and nAChR, there are various signalling systems indirectly targeting the mesolimbic dopamine system with promising preclinical findings on alcohol‐mediated behaviours. Collectively, these data indicate that indirect modulation of dopamine signalling might be a potential target for novel treatment strategies for alcohol dependence and that these targets should be investigated in more detail in human laboratory studies as well as randomized clinical trials. Studies elucidating the underlying mechanism of action of the complex dopamine–alcohol interaction have been conducted. On the other hand, local administration of the dopamine D2 receptor antagonist, sulpiride, into the anterior VTA did not alter alcohol nor sucrose intake in high‐alcohol‐preferring rats [142]. It should also be mentioned that accumbal dopamine D1 receptor might regulate alcohol‐induced reward.

Availability of data and materials

The results demonstrated that treatment with the depot formulation of flupenthixol led to a significant increase in rates of relapse (85.2% on active treatment compared with 62.5% on placebo). A major concern with flupenthixol is results from studies demonstrating an increase in the risk of relapse in rodents as well as humans [146], an effect preferentially observed in males [147]. Overall, the clinical utility of atypical antipsychotics has shown to be of some benefit in patients suffering from alcohol dependence and a concomitant psychiatric diagnosis including schizophrenia [148, 149]. A major challenge, however, with the first‐generation antipsychotic drugs is their severe side effect profile including extrapyramidal symptoms, sedation, cognitive impairment, neuroleptic malignant syndrome, which have limited their use in research and in turn its clinical utility in treating alcohol dependence [150, 151]. Alcohol interacts with serotonergic synaptic transmission in the brain in several ways.

  • An indirect activation of mesolimbic dopamine via accumbal glycine receptors and ventral tegmental nicotinic acetylcholine receptors (nAChRs) appears likely [2, 3], but additional targets has been suggested (for review see [4]).
  • Men and women with lower income or education levels are more likely to develop medical conditions related to alcohol abuse compared to similar individuals with a higher socioeconomic status.
  • He also reviews and advises on policies, procedures, and techniques for treating substance use disorder.
  • For the McGill study, researchers recruited 26 healthy social drinkers (18 men, 8 women), 18 to 30 years of age.
  • In contrast to other stimuli, alcohol-related stimuli maintain their motivational significance even after repeated alcohol administration, which may contribute to the craving for alcohol observed in alcoholics.

Several studies have shown that changes in the DA system in the CNS can influence drinking behaviors both in animals and in humans. Early animal models have shown that injection of the neurotoxin 6-hydroxydopamine (6-OHDA) in the ventricle or in other brain regions destroys dopaminergic neurons. Traditional dopamine D2 receptor antagonists (so‐called neuroleptics, first‐generation antipsychotic drugs or typical antipsychotic drugs) are primary used for the treatment of psychosis, schizophrenia and bipolar disorder [11] based on their ability to counteract a heightened dopamine activity in the brain. It should also be mentioned that these typical antipsychotic agents might have effects on other receptors including dopamine D1, 5HT2 and alpha1 receptors.

Hyperactive Dopamine Response Linked to Alcoholism

Moreover, although increased serotonin levels at the synapses in the brain can moderate alcohol consumption, additional factors contribute to continued alcohol abuse. These atypical antipsychotics have a significantly improved side effect profile compared to the traditional first generation of dopamine D2 antagonists. Thus, there has been a renewed interest in evaluating these medications as potential treatment for alcohol dependence with the assumption that the atypical antipsychotics might reduce craving and consumption alcohol and dopamine of alcohol without the substantial adverse effect profile [152]. Furthermore, they are clinically used for alcohol‐dependent patients during the acute detoxification phase to prevent agitation, hallucinations and delirium tremens [153]. The mesocorticolimbic dopamine system has an established role in driving the rewarding sensations from natural rewards such as food, sex and exercise, which are important behaviours to ensure our survival [6, 7] as well as among drugs of abuse, including alcohol (for review see [8]).

What Is Dopamine?

These findings provide evidence that an “as-needed” prescription of nalmefene may be an effective treatment for alcohol dependence for some. Unlike medications that must be taken every day, the as-needed approach targets medication administration to periods where alcohol use is more likely and may help break the cycle of alcohol dependence and binge drinking. Individuals with low dopamine levels may experience a loss of motor control, such as that seen in patients with Parkinson’s disease. They can also develop addictions, cravings and compulsions, and a joyless state known as “anhedonia.” Elevated levels of dopamine can cause anxiety and hyperactivity. Some experiments found no difference in DA release in the NAc after intraperitoneal injection of ethanol between P and NP rats. For example, Yoshimoto and colleagues[11] and Gongwer and colleagues[23] found that although HAD and LAD rats differed in their basal level of extracellular DA, they did not differ in CNS DA release after intraperitoneal injection of ethanol.

  • Two key neurotransmitters that interact with the serotonergic system are gamma-aminobutyric acid (GABA) and dopamine.
  • These atypical antipsychotics have a significantly improved side effect profile compared to the traditional first generation of dopamine D2 antagonists.

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