Biology 202
1998 First Web Reports
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Neurobiological Mechanisms for Alcoholism

Akino Irene Yamashita

While alcohol could well be considered the most socially acceptable psychoactive drug in our society, the dangers of alcohol abuse and addiction are well known. However, not everyone who uses, or even abuses, alcohol will actually become an alcoholic who is physically dependent on the drug. Not all of the mechanisms that cause one to become addicted to alcohol have been clarified. However, there seem to be two main reasons for alcohol addiction. One is that the chronic consumption of alcohol causes changes in the brain that result in a dependence on alcohol. Another is that some individuals have abnormalities in their brains that result in a greater tendency to become addicted to alcohol. The report in 1990 of the discovery of an "alcoholism gene", while not fully supported by subsequent studies, is illustrative of many observations that the brain chemistry of alcoholics is different from nonalcoholics.1

The acute effects of alcohol on the brain result mainly from its effects on the postsynaptic receptor sites for various neurotransmitters.2 The depressant effects of alcohol arise from its action on GABA-A receptors, the principal postsynaptic receptors for the inhibitory neurotransmitter GABA. When stimulated by GABA, these receptors respond by opening an ion channel that allows Cl- ions to enter the neuron, which hyperpolarizes the membrane and reduces the chance for an action potential to occur. These receptors are also sensitive to alcohol, and its presence allows even more Cl- ions to enter the cell, resulting in further inhibition.3

However, the effects of the chronic use of alcohol are quite different, and result in a decreased sensitivity of GABA-A receptors to both alcohol and GABA itself. Alcohol appears to actually change the genetic makeup of the neuron and thus change the structure of the receptor proteins generated by the cell. This manifests itself as increased tolerance to the effects of alcohol, since more of the drug is required to achieve the same depressant and intoxicating effect.4 Because of the damage to the function of the GABA inhibitory system, the CNS tends toward hyperexcitability, resulting in the anxiety, tremors, disorientation, and hallucinations associated with alcohol withdrawal. Chronic exposure to alcohol may also increase the sensitivity of glutamate receptors, and since glutamate is an excitatory neurotransmitter this would contribute further to CNS hyperexcitability.5

Alcohol also seems to affect the binding properties of receptors for opioid peptides, as well as the synthesis of these peptides. Specifically, alcohol may stimulate the release of <beta>-endorphins, neurotransmitters held responsible for euphoria and anesthesia, accounting for some of the intoxicating effects of alcohol.6 The experimental observation that the administration of opioid blockers reduces craving for alcohol has led to FDA approval of naltrexone, a drug that interferes with the function of opioid receptors, as a treatment for alcoholism.7

Thus, alcohol can cause physical addiction directly through its effects on many receptor sites in the postsynaptic membranes of neurons. However, another important factor in the development of alcoholism appears to be that the brains of alcoholics have abnormal neurotransmitter systems, especially in the mesocorticolimbic dopamine system. This system consists of dopamine-releasing neurons connecting the ventral tegmentum (VTA) of the midbrain to the medial prefrontal cortex and the nucleus accumbens (NAC) in the limbic system. It is often called the "reward system" because it transmits inputs that lead to a sensation of reward for euphoria when processed in the limbic system.8 GABA and the opioid peptide neurotransmitters are active in the VTA and NAC, and play a role in regulating the dopaminergic system.9 The neurotransmitter serotonin, present in the hypothalamus, also seems to affect the system by regulating the activity of dopamine.10

However, the brains of alcoholics seem to contain abnormalities that reduce the effectiveness of the dopaminergic system. Alcohol consumption may compensate for these deficiencies, for alcohol, whether directly or indirectly through its effects on the receptors of neurotransmitters affecting the dopaminergic system, causes an increase in the amount of dopamine released in the limbic system.11

Studies of strains of rats bred to prefer alcohol to water show that these "alcoholic" rats have fewer serotonin-releasing neurons in the hypothalamus, higher levels of opioid peptides in the hypothalamus, more GABA neurons in the nucleus accumbens, inhibiting the release of dopamine, a reduced supply of dopamine in the nucleus accumbens and a lower density of dopamine D2 receptors in certain areas of the limbic system when compared to normal rats.12 Some studies have indicated serotonin levels 10-30% lower than normal, dopamine levels 20-30% lower, and 20% fewer D2 receptors.13 D2 receptors are postsynaptic dopamine receptors found in the midbrain, caudate, and limbic systems.14

When drugs that stimulated serotonin release, or directly stimulated D2 receptors were administered, alcohol consumption decreased, while the administration of D2 dopamine-receptor antagonists increased consumption.15 The observed increase in dopamine release after the consumption of alcohol is also much higher in alcohol-preferring rats than in non-preferring rats, suggesting that the brains of alcohol-preferring rats are much more sensitive to the effects of alcohol.16

These findings have also been replicated to some extent in humans. Levels of serotonin metabolites in the cerebrospinal fluid of alcoholics have been shown to be lower than normal.17 Alcoholics given serotonin and dopamine precursors in clinical trials reported fewer cravings for alcohol, less stress, and had an increased likelihood or recovery and a reduction in relapse rates.18

The genetic marker that has been suggested to be indicative of a genetic predisposition to alcoholism is also related to the dopaminergic system. It is the A1 allele of the gene for the dopamine D2 receptor. The original 1990 study by Blum et al was a post-mortem of 35 alcoholics and 35 non-alcoholics, and found the A1 allele to be present in 69% of the alcoholics as opposed to 20% of the non-alcoholics. The alcoholics had repeatedly failed treatment, and many of the deaths were alcohol-related. Subsequent studies have generally upheld the initial results, though some have refuted them. One hypothesis is that the A1 allele codes for a lower density of D2 receptors than the more common A2 allele, resulting in an inherited deficit in brain reward mechanisms.19

The neurobiological mechanisms for alcoholism discussed here of course are not definitive, and as in most diseases with behavioral manifestations inherent biological abnormalities may contribute to the expression of the behavior but are not the only factors involved. The A1 allele, for example, has also been associated with other addictive disorders such as abuse of other drugs, compulsive overeating, and pathological gambling, as well as neurological disorders such as ADD and Tourette's syndrome.20 This suggests that the A1 allele may predisposes a person to addictive behavior in general, and is not specific for alcoholism. However, the general experimental evidence seems to indicate that many individuals are neurobiologically more likely to develop alcoholism than others.*


1. American Scientist Article: Reward Deficiency Syndrome

2. OTA Report: Biological Basis for Substance Abuse and Addiction

3. Center Line Vol 8 No 3

4. Ibid.

5. OTA Report

6. SPRINGER LINK - Psychopharmacology - Abstract Volume 129 Issue 2 (1997) pp 99-111

7. OTA Report

8. Ibid.

9. American Scientist

10. OTA Report

11. American Scientist

12. Ibid.

13. OTA Report

14. Honours Thesis by Karen Johnson, UNSW Australia 1996

15. American Scientist

16. OTA Report

17. Ibid.

18. American Scientist

19. Honours Thesis
(visit this site for a comprehensive listing of major studies on this subject)

20. American Scientist

Web sites not cited directly but used as reference:

Center Line Vol 7 No 3

Center Line Vol 8 No 1


Researchers Discover Probable Molecular Site Of Alcohol And Anesthetic Actions

ASAM: American Society of Addiction Medicine

This paper reflects the research and thoughts of a student at the time the paper was written for a course at Bryn Mawr College. Like other materials on Serendip, it is not intended to be "authoritative" but rather to help others further develop their own explorations. Web links were active as of the time the paper was posted but are not updated.

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