Journal of the Psychiatric
Association of Thailand
บรรณาธิการ มาโนช หล่อตระกูล
Current Advance in Alcohol Research
Alcohol is the
most frequently used brain depressant. Excessive consumption
of alcohol is a major public health concern. Insights in
alcohol research largely have developed during recent years
and had enormous impact on medical scientific field. This
paper seeks to explore the current advances in alcohol research.
These advances present indicative of the future promise
of neuroscience research to solve many questions concerning
how alcohol addiction develops, and how it can be successfully
prevented and treated.
Assoc Thailand 1998; 43(2): 159-66.
2541; 43(2): 159-66.
In most cultures, alcohol
is the most frequently used brain depressant. At some time in their
lives, as many as 90% of adults in the United States have had some
experiences with alcohol, and a substantial number (60% of males
and 30% of females) have had one or more alcohol related adverse
life events(1). Excessive consumption of alcohol is a major public
health concern worldwide. Tremendous insights in alcohol research
largely developed in recent years. These advances which have had
enormous impact on medical scientific field include:
- advance in genetic
- the application
of neuroscience to understanding drinking and the phenomena
- how alcohol damages
- the development
of new approaches to treatment and prevention.
Advance in genetic
Research on the genetics
of alcoholism is still in the formative stage; nevertheless, a tremendous
amount of work has been accomplished, and many tentative conclusions
appear not only possible but reasonable.
Familial studies have
demonstrated that the incidence of alcoholism is higher in families
of alcoholic than in the general population. Sons of alcoholics
are approximately 3-5 times more likely to become alcoholic than
are sons of non alcoholics(2). The significance of this proportion
has led to the possibility that the etiology for alcoholism to run
in families is genetically determined(3,4,5). Twin studies for the
most part have shown concordance for alcoholism to be greater in
identical (monozygotic) twin-pairs than the concordance for alcoholism
in fraternal (dizygotic) twin-pairs(6,7,8,9). In order to assess
the relative contribution of genetic and environmental factors to
the development of alcoholism, investigators have analyzed drinking
patterns in adopted children of alcoholics and non-alcoholics. Sons
of alcoholics, adopted by non-alcoholic families in early life,
are 3 times more likely to become alcoholic than are similarly adopted
sons of non-alcoholics (10,11,12).
The combination of family,
twin, and adoption studies offers enough support for genetic factors
to justify a search for what might be inherited to increase the
risk for this disorder. As a result, a number of laboratories have
begun to look for trait or phenotypic markers of a vulnerability
Phenotypic markers can
be defined as molecular, biochemical, physiological or behavioral
patterns of response to alcohol that can be shown to genetically
associated with alcoholism. In the current use of animal models
and the approaches of Qualitative Trait Loci (QTL) mapping to find
locations in the mouse genome that may have synonymy with the human
genome, it is interesting that a number of candidate loci are located
in the 4q, 9q, and 13q chromosomal regions (Table 1) (13,14,15,16).
dehydrogenase I (ADH1)
dehydrogenase III (ADH3)
2 receptor (5HT2)
Table 1. Relationship
between candidate loci and phenotypic markers.
The application of
neuroscience to understanding the phenomena of alcohol addiction
of technologies and techniques of neuroscience has been brought
to bear on understanding the consumption of alcohol and related
behavioral phenomena of addiction, that is, tolerance; withdrawal;
impair control over drinking ; and craving.
Ethanol diffuses into
cell membranes and increase membrane fluidity. After chronic exposure
to ethanol, cellular membranes become resistant to the fluidizing
effect(17). In addition, there are also acute and chronic ethanol-induced
changes in many membrane component and functions; membrane lipids
and phosphatidylinositol, receptors, second messengers, GTP binding
proteins, neuromodulators, ion channels, transporters, and protein
whose gene expression is altered by ethanol. Many of these membrane
components are acutely affected by ethanol and later exhibit tolerance
when rechallenged (18,19,20,21,22,23,24).
Research has found many
effects of different receptor system, such as NMDA; of nitric oxide;
and especially of the cytokine network that has now been shown to
be involved in the action of alcohol. The excitatory NMDA receptor
in the hippocampus appears to play a role in learning and memory,
and is exquisitely sensitive to ethanol. The voltage-dependent calcium
channel is also a major target for the acute and chronic effects
of ethanol. The increased number of voltage-dependent calcium channels
found after chronic exposure to ethanol involves regulation by protein
kinase C and may play a role in alcohol withdrawal seizures. Indeed,
mice genetically prone to develop ethanol withdrawal seizures exhibit
an increase in voltage-dependent calcium channels. Abnormal sensitivity
to ethanol or altered regulation of these membrane-dependent events
by ethanol could play a role in a genetic predisposition to alcoholism(25,26,27,28,29).
cAMP signal transduction
is a second messenger system that undergoes acute and chronic adaptive
responses to ethanol. Adenosine is an inhibitory modulator that
appears to mediate many acute and chronic effects of ethanol in
the nervous system(30).
indicated the potential involvement of several neurotransmitter
and neuromodulator systems, such as serotonin, dopamine, and g aminobutyric
acid (GABA), in abnormal alcohol drinking behavior. The benzodiazepine/GABA
receptor complex appears to be a major target for ethanol, exhibiting
cross-tolerance with BZD and barbiturates. Differences in GABAA-activated
Cl- channel function have recently been found in animal
with differential genetic sensitivity to the hypnotic effect of
Also, attention has focused
on the endogenous opioid system as a possible mediator of alcohol
drinking. There are at least three possible mechanisms by which
alcohol can enhance opioid receptor activity. First, the alcohol
metabolite, acetaldehyde, can combine with catecholamines to form
the alkaloid tetrahydropapaveroline(THP). THP can convert to tetrahydroisoquinoline
alkaloids(TIQS), which are opioid receptor agonists and
directly lead to morphine-like effects. Second, Alcohol can stimulate
the release of b endorphin or enkephalins, and thus indirectly stimulate
opioid receptor activity. However, this action may be specific to
only people at risk for alcohol dependence because of a positive
family of alcoholism. Third, alcohol can directly enhance the sensitivity
of the opioid receptors to endogenous opioids by altering membrane
Another interest is focused
on Arginine vasopressin(AVP), a mammalian antidiuretic hormone.
It was shown that in animal studies the administration of AVP will
maintain (reduce the rate of loss of) functional ethanol tolerance,
once that tolerance has been acquired, even in the absence of further
ethanol intake by the animals. This action may be related to the
effect of AVP on c-fos expression in the lateral septum(33,34).
How alcohol affects
Many discoveries have
been made about the toxicology of alcohol in the brain, heart, liver,
gastrointestinal tract, marrow, breast tissue and especially in
the developing fetus(35,36,37,38,39). Recently, acetaldehyde, the
first metabolite of ethanol is recognizing as an animal carcinogen
and is suspected to be the key chemical in alcohol-related cancer(40).
Another aspect of toxicology is its converse, the fact that while
alcohol harms body tissues. It also has protective effects on coronary
circulation, and possibly prevent osteoporosis in postmenopausal
women. These diverse and sometimes conflicting findings have served
to stimulate further scientific study of how much drinking either
endangers or benefits the health of both men and women(41,42).
The development of
new approach to treatment
The search for new pharmacological
adjuncts for the treatment of alcohol dependence is motivated by
the limited effectiveness of current psychosocial and pharmacological
treatments. Psychosocial treatments are associated with only modest
success rates(43). Combining pharmacological and psychosocial treatments
has limited clinical usefulness because the medications either are
ineffective or have low level of patient compliance. The recent
focus in alcoholism treatment research is the development of new
pharmacotherapy. Naltrexone, an opiate antagonist, in the United
States and acamprosate (calcium bisacetylchromotaurinate), a GABA
agonist, in Europe are the most interesting examples(44,45,46).
Many studies suggest that either naltrexone or acamprosate effectively
reduces the rate of alcoholic relapse and the level of craving for
alcohol. Naltrexone apparently exerts its beneficial effects by
reducing the high that is associated with alcohol consumption.
In addition, both of these drugs appear to be safe in the alcohol-dependent
population, and they are associated with only few side effects.
If the efficacy suggested by these data is replicated in additional
studies, it may be concluded that these drugs demonstrate many of
the qualities hoped for in an ideal pharmacological treatment for
Another growing interest
in treatment area has been focused on objective markers of heavy
alcohol consumption since individuals do not always report accurately
on the amount that they drink. Several biochemical markers are used
clinically to indicate if a patient has a drinking problem. Among
those in current use are blood ethanol, mean erythrocyte volume,
high-density lipoprotein cholesterol,?g -glutamyltranspeptidase,
and carbohydrate-deficient transferrin(47,48). Recently, all of
these have drawbacks in diagnostic sensitivity and/or specificity.
Phosphotidylethanol (PEth) is being investigated as another new
biochemical marker of excess alcohol intake.
PEth is a unique phospholipid
that is formed in cell membranes only in the presence of ethanol.
In humans, basal PEth formation has been observed in neutrophil
granulocytes of alcoholic patients up to 24 hours after the latest
alcohol intake, when blood ethanol concentration was 0 (49). Investigators
are now exploring ways of utilizing this test to better detect hidden
heavy alcohol use and to monitor alcoholics during treatment and
Alcohol abuse and alcoholism
are serious social problems with both biological and behavioral
elements. Investigating how the brain affects behavior is the one
of greater challenges facing alcohol research over the next decade.
All the new techniques of neuroscience are being used to further
our understanding of the fundamental phenomena of alcohol use and
abuse. How alcohol influences the variable expression of receptor
subunits and how the initial pattern of subunits affects sensitivity
to alcohol both under study. The toxic effects of alcohol on the
structure and function of various organs are being explained. Subtle
aspects of cognitive impairment are being studied with sophisticated
tests combined with imaging. Important insight into the specificity
of ethanol action at various receptors have revolutionized thinking.
This contemporary work presents indicative of both the success of
science in understanding brain, behavior and biology, and the future
promise of neuroscience research to solve many questions concerning
how alcoholism develops, and how it can be successfully prevented
and treated. To formulate rational social policy in the future,
it is necessary to know all details of its actions,
not just one side of it.
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