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Neuropharmacology of Alcohol

Alcohol is one of the oldest and most widely used drugs on earth. Its use predates recorded history and may go back as far as the Paleolithic age, around 8000 B.C. References to its use appear in the Bible and in ancient Egyptian pictograms, and alcohol has been a part of American culture since the Pilgrims landed at Plymouth Rock, Massachusetts. In the last decade, neuroscience has significantly increased our understanding of the neuropharmacological effects of this drug. As a psychoactive drug, alcohol causes changes in brain chemistry that affect a wide range of behaviors.

What is Alcohol?
The modern use of the term "alcohol" describes various compounds composed of carbon, hydrogen and oxygen. The three most commonly encountered alcohols are: methyl alcohol (methanol), isopropyl alcohol (isopropanol) and ethyl alcohol (ethanol). All alcohols have a similar chemical structure and always contain a hydroxyl group, "OH", attached to a carbon molecule, which itself is connected to various combinations of carbon and hydrogen molecules.

Methanol is found in windshield wiper fluids and de-icers, antifreeze, glass cleaner, canned heat, paints, varnishes, and paint thinners and removers. Its toxicity results from its metabolism to formaldehyde and then to formic acid, a cellular toxin that is extremely poisonous. The accumulation of formic acid produces severe metabolic acidosis. Six to seven ounces of methanol is lethal for most adults, and much smaller quantities can cause permanent damage to the retina.

Isopropanol, common rubbing alcohol, is also quite toxic. Small amounts, as little as several ounces, can cause permanent damage to the visual system, and eight ounces is usually lethal. Some alcoholics may consume methanol or isopropyl alcohol, intentionally or unknowingly, with potentially lethal consequences.

Ethanol, the subject of this review, is the alcohol in alcoholic beverages consumed by many people. From this point, the term "alcohol" will be used to denote ethanol.

Alcohol is a relatively simple compound, with the general chemical formula C(2)H(5)OH. It is a clear, relatively odorless liquid that is infinitely mixable in water. Alcohol is metabolized by the enzyme alcohol dehydrogenase to acetaldehyde, an adrenergic toxin, which in turn is rapidly metabolized by another enzyme, aldehyde dehydrogenase, to acetic acid, and eventually to carbon dioxide and water. Understanding the biochemistry of alcohol metabolism has helped to develop treatments for alcohol abuse. For example, the drug Antabuse7 inhibits aldehyde dehydrogenase allowing a toxic accumulation of acetaldehyde to occur when alcohol is consumed. Acetaldehyde causes nausea and discomfort. This aversive reaction is the basis of some aversion therapies.

Alcohol Concentrations
When yeast, water, and sugar are together, the yeast recombines carbon, hydrogen, oxygen, and water to form alcohol and carbon dioxide. Each molecule of glucose is converted to two molecules of alcohol. This process is referred to as fermentation. Different alcoholic beverages are derived from the use of different fermenting ingredients. For wines, sugar- rich fruits provide necessary sugar for fermentation. This process continues naturally until alcohol concentrations of about 15-20% are reached. At that concentration, alcohol is so high that the yeast dies.

Beers are manufactured with a different source of sugar--namely, the starch found in cereal grains, which is enzymatically converted to sugar through a malting process that allows fermentation to occur. For beers, fermentation is intentionally stopped when the alcohol concentration reaches about 3-6 percent, and for wines, the process is typically terminated at concentrations of about 11-13%. Since alcohol boils at a lower temperature than water, the two can be separated through distillation. In this process, fermented alcohol is heated, and the escaping alcohol vapors are cooled, so that they condense and can be collected.

Distilled spirits can be made to very high alcohol concentrations (typically 50-60% in some beverages and up to nearly 100% in other products). The percent of alcohol by volume is ½ the listed proof --e.g., 80 proof = 40% v/v (volume of alcohol per volume of solution).

From a scientific perspective, a 5-ounce glass of wine (12% v/v), a 12-ounce beer (4.9% v/v) and a shot or mixed drink containing 1½ ounces of 80 proof spirits (e.g., whiskey, vodka, gin) each contain the same amount of absolute (100%) ethanol. However, the concentration of alcohol in the human body is a function of the number of grams of alcohol consumed, the amount of body water in the person, and other biological factors, such as absorption and metabolism.

Blood Alcohol Concentrations
The concentration of alcohol in blood, serum, water or any other liquid is the quantity by weight of absolute alcohol in a fixed volume of fluid. For example, 0.08% (w/v) is the same as 80 milligrams per 100 cc of fluid. Some clinical laboratories (hospitals) may report alcohol concentrations in serum, rather than whole blood. Because of differences in water content, in most cases, serum alcohol is about 15-16% higher than whole blood alcohol concentrations.

Neurochemistry of Acute Alcohol Intoxication
Regardless of the type of alcoholic beverage consumed, it is the psychoactive drug, ethanol, which produces effects on the brain leading to subsequent alteration of behavior and influencing virtually all cells within the body. The degree of alcohol's effects is determined by the concentration in blood, which is influenced by the amount and rate of alcohol consumption, bioavailability due to factors such as rate of absorption, the biotransformation of alcohol, which may be influenced by genetic factors, and drinking experience. All of these factors ultimately result in individual differences in the exposure and response of various cells to alcohol.

Two specific neurochemical systems in the brain have been strongly implicated in causing alcohol intoxication: 1) gamma aminobutyric acid (GABA) and its receptor; and 2) glutamate, and one of its receptors, which is termed N-methyl-D-aspartic acid (NMDA). GABA is the major inhibitory neurotransmitter in the brain, and interacts with receptors that recognize it. These receptors also recognize benzodiazepines, related drugs. When these receptors are activated by their specific neurotransmitter, cellular activity changes. For example, benzodiazepines, which share many biobehavioral properties with alcohol, enhance chloride ion transport through the GABA(A) receptor, causing a decrease in neuronal activity.

Drugs that mimic the effects of GABA enhance and prolong the behavioral effects of alcohol. Those drugs that block the effects of GABA have the opposite effects. For example, highly specialized drugs called benzodiazepine receptor inverse agonists, antagonize (block) many alcohol-induced cognitive, behavioral and neurophysiological effects of alcohol in animal models. Such research suggests that alcohol produces its effects by enhancing chloride ion transport resulting in a decrease in neuronal activity within neurons that use GABA.

Glutamate, the major excitatory neurotransmitter in the brain, is also believed to play an important role in alcohol intoxication and behavior. Blocking NMDA receptors has similar behavioral effects to alcohol. Also, electrophysiological studies have shown that alcohol antagonizes NMDA-induced behavioral responses. Together, such findings suggest that the inhibition of NMDA receptors is an important mechanism by which acute alcohol consumption affects brain function and behavior.

Neurochemistry of Chronic Alcohol Intoxication
Since alcohol shares pharmacological actions with benzodiazepines and barbiturates, including cross-tolerance and dependence, this suggests that all three drugs share some neuropharmacological mechanism(s) of action. Possibly tolerance to the sedative and intoxicating effects of alcohol is the result of a compensatory decrease in GABA-mediated inhibition in the brain. Recent studies suggest that changes in certain GABA receptor channels also contribute to the signs and symptoms of the ethanol withdrawal syndrome.

Decreases in neuron activity produced by GABA and increased sensitivity of NMDA receptors may account for symptoms of alcohol withdrawal. Some research suggests that only a few days of chronic alcohol exposure may produce supersensitive NMDA receptors. Those brain changes may contribute to the behavioral hyperexcitability and seizures that accompany withdrawal.

Naltrexone, a drug that antagonizes opiate receptors, has been shown to be effective in reducing relapse. This suggests that alcohol and opiates share some common mechanisms. Another drug, acamprosate, a drug that modulates both glutamate and GABA systems, decreases craving and may be a promising treatment for alcoholism.

With a clearer picture of when and where neuropharmacological changes occur in the brain, future research on the neurophysiological mechanisms that mediate these effects may lead to effective pharmacological adjuncts to treatment and prevention of alcohol-related problems.

References
Brick, J. (2003) The characteristics of alcohol: chemistry, use and abuse. In J. Brick (Ed.), Handbook of the medical consequences of alcohol and drug abuse (pp 1-11). New York: Haworth Medical Press.

Brick, J., and Erickson, C. (1999). Drugs, the brain and behavior: The neuropharmacology of abuse and dependence. New York: Haworth Medical Press.

Crews, F. (2003). The effects of alcohol abuse on the brain. In J. Brick (Ed.), Handbook of the medical consequences of alcohol and drug abuse (pp 165-266). New York: Haworth Medical Press.

Pohorecky, L. and Brick, J. (1990). The pharmacology of ethanol. In International encyclopedia of pharmacology and therapeutics. Section 130: Psychotropic drugs of abuse (pp. 189-254). New York: Pergamon Press.

Center of Alcohol Studies 
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8 2004

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