Alcohol and alcoholism (Oxford, Oxfordshire). Supplement最新文献

Animal studies have shown that alcohol consumption is reduced when serotonin (5-hydroxytryptamine, 5-HT) levels are increased in the central nervous system. Similarly, studies of alcohol-dependent human subjects have shown that treatment with 5-HT reuptake inhibitors (i.e. zimeldine, citalopram, fluoxetine, and fluvoxamine) decreases the desire to drink alcohol and improves symptoms of alcohol-related anxiety and depression in patients who have undergone detoxification. However, not all studies have shown them to be an effective treatment to help maintain recovery in alcohol dependence. The exact mechanisms of action of the 5-HT reuptake inhibitors are not yet fully understood and additional studies are needed. However, at this time, the 5-HT reuptake inhibitors may be effective pharmacotherapies for alcohol-related depression.

Animal studies have demonstrated that alcohol changes neurotransmitter concentrations in the brain. These changes in levels of dopamine, serotonin, gamma-aminobutyric acid (GABA), endogenous opioid peptides, and noradrenaline are associated with activation of reward centres in the brain. It is this property of alcohol that is believed to be responsible for the reinforcing effect of alcohol consumption in rats. One class of neurotransmitters, the endogenous opioid peptides, are believed to play an important role in alcohol reinforcement. This view is supported by the reduced preference for alcohol consumption found in rats given an opiate agonist. The widely distributed inhibitory neurotransmitter GABA is also believed to play a fundamental role in mediating the effects of alcohol. A better understanding of the mechanisms that support alcohol dependence in animals offers hope for the development of pharmacological interventions to block these mechanisms, an approach that is now being explored in humans.

Numerous neurotransmitter systems [e.g. dopamine, gamma-aminobutyric acid (GABA), the endogenous opioids, and serotonin (5-hydroxytryptamine, 5-HT)] are involved in the regulation of alcohol consumption. Because 5-HT reuptake inhibitors and opioid antagonists modify the activity of neurotransmitters, it has been hypothesized that they may also mediate the desire to drink alcohol by acting on specific receptors in the brain. Animal studies have shown that concomitant administration of 5-HT and opioid antagonists reduces alcohol consumption; therefore, the combined use of several pharmacotherapies may be the most effective treatment for alcohol dependence.

The US National Institute on Alcohol Abuse and Alcoholism (NIAAA) recognizes two forms of problematic drinking: 'willful alcohol abuse', a behavioural problem, and 'alcohol dependence', a true medical disorder, which includes a genetic component, that can be scientifically understood and medically treated. Current biomedical research has linked specific neurotransmitters to certain effects of alcohol that are unique to alcoholics. An inadequate flow of information between the victims of alcoholism, researchers, and the public has impeded further exploration of the genetic and neurochemical underpinnings of alcohol dependence. This is due in part to continuing misconceptions about alcohol dependence, not only among the general public, but within the scientific and medical communities as well. Consequently. compared to other diseases, research in alcohol dependence is proceeding with less urgency despite its relatively high economic and social costs. Incorporating the input of recovering alcoholics into future research agendas can help to ensure relevant scientific investigation and the delivery of a more accurate and consistent message to the public with regard to alcoholism.

Specific laboratory tests can be used to identify patients who are alcohol-dependent. The laboratory values of a number of biological 'markers', including carbohydrate-deficient transferrin, are often elevated in cases of chronic and acute alcohol abuse. Trait markers reflect a predisposition for alcoholism; state markers reflect actual alcohol consumption. It has been suggested that state markers can be subdivided into screening and relapse markers, and even further subdivided into pre-relapse markers, i.e. craving markers. We hypothesize that methanol metabolism and the presence of condensation products in the blood may serve as state and pre-relapse markers for alcoholism. Since the sensitivities and specificities of laboratory screening tests vary, and an absolute marker for alcoholism has yet to be identified, research in the area of biological markers for alcoholism should continue.

We investigated the endogenous opioid system and its role in mediating the reinforcing effects of ethanol that lead to high ethanol consumption as a biochemical marker of an individual's vulnerability to excessive ethanol consumption. We performed studies using human subjects with [high risk (HR)] and without [low risk (LR)] a family history of alcoholism to supplement our studies with experimental animals bred selectively for high- or low-ethanol consumption. HR subjects had lower basal plasma beta-endorphin levels as compared with LR subjects, but they had a more pronounced release of beta-endorphin after exposure to ethanol. Findings from animal studies indicated that ethanol-preferring (C57BL/6) mice (analogous to the HR human subjects) had higher levels of hypothalamic beta-endorphin activity than did ethanol-avoiding (DBA/2) mice (analogous to the LR human subjects) under basal conditions. However, the C57BL/6 mice had a more pronounced release of hypothalamic beta-endorphin than did DBA/2 mice after exposure to ethanol. Thus, although hypothalamic beta-endorphin system activity in human and animal models of alcoholism differs under basal conditions, there is enhanced hypothalamic beta-endorphin system activity after exposure to ethanol in both models. We have also performed studies comparing the density and distribution of opioid receptors in brains of ethanol-preferring animals, such as C57BL/6 mice and ALKO-alcohol (AA) rats, and ethanol-avoiding animals, such as DBA/2 mice and ALKO-non-alcohol (ANA) rats. Interestingly, it was observed that in distinct brain regions known to be important for mediating the process of reinforcement, the C57BL/6 mice had a higher density of delta-opioid receptors than the DBA/2 mice, while the AA rats had a higher density of mu-opioid receptors than the ANA rats. Thus, in the ethanol-preferring animals, the increased release of beta-endorphin following exposure to ethanol was associated with a higher density of delta- or mu-opioid receptors in brain regions important for reinforcement, such as the nucleus accumbens and the ventral tegmental area, and may interact with the dopaminergic system and promote ethanol's reinforcing properties, leading to excessive drinking and alcoholism.