by Carrie Sha
It’s a Friday night. House parties. Drinking games. Red solo cups. It’s a common sight. But where does the college drinking culture come from and where can we draw the thin line between being in control of alcohol and having alcohol control you? Approximately one out of five college students meet the National Institute on Alcohol Abuse and Alcoholism’s criteria for alcohol dependence (1). Even those who don’t drink can be one of the 599,000 students that are often unintentionally injured in alcohol-related situations (1). One of the causes behind these alarming statistics is simply the biology of the adolescent brain. College is usually where the last stage of brain development, the maturation of the prefrontal cortex, takes place. The prefrontal cortex is a region key to control and decision-making. Coupled with academic stress and the pressure to succeed, especially in the nation’s top-notch universities, it is no wonder that drinking gets out of control quickly. What is the science behind the addictive nature of the simple ethanol molecule, the key ingredient in drinking alcohol, and what are current researchers doing to tame its effects? Professor Gutlerner, lecturer in Biological Chemistry and Molecular Pharmacology at the Harvard Medical School, explains.
Science of Addiction
Why is the ethanol molecule so addictive? Ethanol (C2H5OH) first binds to a GABA-a receptor respon- sible for creating gamma-aminobutyric acid (GABA). GABA inhibits neuron activity by an increase of chlorine ion release into neurons. (2,3). This dramatic increase in negative charge causes the membrane potential of the neurons to be very negative, thus making it difficult for neurons to cross the threshold membrane potential required for activation. To a similar effect, alcohol inhibits glutamate, the counterpart molecule to GABA used to excite neuron activity. The combined consequences of GABA stimulation and glutamate inhibition cause the calming effects of alcohol that is typically associated with an “optimal buzz.” However, Professor Gutlerner cites that prolonged alcohol use makes the GABA-a receptor less sensitive to activation, which is partially responsible for many of the effects during alcohol withdrawal such as anxiety disorders, panic attacks- the combined result of a hyper-activated central nervous system. As a result, many addicts find themselves drinking to simply feel “normal.”
Reward Pathway
Although the damage to the GABA pathway is important, a significant consequence of alcohol is its interference with the reward pathway. The reward pathway is essentially nature’s way of reinforcing good behaviors and eliminating bad behaviors by generating the neurotransmitter dopamine in the ventral tegmental area (VTA), a group of neurons located in the midbrain. Alcohol’s major interaction with the reward pathway comes through its stimulation of beta-endorphins, which activates opioid peptides, a chain of amino acids that modify the activity of nearby neurons (4). These peptides control feelings of euphoria. Alcohol also increases the concentration of neurotransmitter dopamine, which stimulates desire in the body’s reward center, the nucleus accumbens, an area not too far away from the VTA. Simultaneously, alcohol binds to acetylcholine and serotonin (responsible for inhibition) receptors and alters their respective pathways. After pro- longed use, more and more alcohol is needed to achieve the same level of euphoria as before. The changed neurochemistry of the addict’s brain can be seen following figure, showing the increase of positive reinforcement in the nucleus accumbens in non-dependents and the increase of negative reinforcement in the amygdala independents.
Vulnerability of the teenage brain
Although there has been conflicting evidence over the degree to which age impacts decision-making and its impact on the vulnerability of young adults to various addictions, many researchers subscribe to a top-down impulse control model of alcohol addiction (5). Physiologically, the teen- age brain is in its last stage of development, the maturation of the pre-frontal cortex. This developmental stage makes decision-making and emotional control especially difficult, supporting the top-down impulse control model and the fact that statistically, younger people are more “likely to try and become addicted to alcohol” (Gutlerner).
Stress
Although “stress” is now a common word to describe all aspects surround- ing college life, it has deep physiologi- cal roots. The stress response is seen in the activation of the hypothalamic- pituitary-adrenal axis (HPA), which increases the production of corticotro- pin releasing factor (CRF), the mol- ecule that generates the fight or flight response in all animals (6). The opi- oid pathway is highly integrated with the control of stress responses in the body. Because of alcohol’s alterations on the opioid pathway, alcohol addicts are constantly hypersensitized to stress during withdrawal, meaning that they are more aware and impacted by their stress level. In turn, this stress makes them more likely to drink. In other words, it’s a vicious cycle.
Current strategies
There is a group of drug therapies aimed at attacking GABA receptors and the dopamine and serotonin pathways. For example, Baclofen is an approved GABA agonist for seizures that has shown to decrease craving and anxiety in alcohol addicts (7). Similarly, a low dosage of topira- mate, a natural anticonvulsant, can be used to dampen down excitability and maintain abstinence by reducing the amount of dopamine produced in the reward pathway during alcohol consumption (8).
Another series of perhaps more effective drugs directly target the reward pathway. For example, Naltrexone is an opioid drug that blocks opioid receptors. Its interfer- ence with the dopamine pathway was reported in 1997 (9), and a series of subsequent clinical trials have shown a high degree of efficacy (10).
Perhaps the most effective drug so far is Antabuse, the first drug approved by the USDFA to treat alcohol addiction. The goal of Antabuse is to simulate alcohol intolerance in addicts by acting as an acid aldehyde inhibitor. Usually, alcohol in the body is metabolized to acetic acid by enzyme called acid aldehyde dehydrogenase. A large database study found that East Asian populations were shown to have a low tolerance to alcohol because of a polymorphism for the inactive form of dehydrogenase. Their intolerance to alcohol, expressed by face flushing and digestive problems, also gave them control over their drinking. Thus, Antabuse, working as an acid aldehyde inhibitor, attempts to achieve the same intolerance to alcohol.
Professor Gutlerner cites that not all these drugs have been so effective. She stresses the importance of psychotherapy in combination with medical approaches, “When improvement is shown in alcohol programs, it frequently comes with psychotherapy combined with medicine. Psychotherapy helps addicts learn to better manage their decision making, and only with this self-control can we see a significance drop in relapse.”
References
1. National Institute on Alcohol Abuse and Alcoholism. 2013. College Drinking Fact Sheet.
2. Yamashita, AI. 1998. Neurobiological Mechanisms for Alcoholism. Bryn Mawr College.
3. Bardi JS. 2002. Tragedy of Alcohol Abuse Drives TSRI Researcher’s Work. The Scripps Research Institute News and Views 2(6).
4. Froehlich JC. 1997. Opioid peptides. Neu- rotransmitter Review 21: 132-135.
5. Winters KC. 2008. Adolescent Brain Devel- opment and Drug Abuse.
6. Smith SM, Vale WW. 2006. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin. Neurosci. 8: 383-95.
7. Garbutt JC, Kampov-Polevoy AB, Gallop R, Kalka-Juhl L, Flannery BA. 2010. Efficacy and safety of baclofen for alcohol dependence: a randomized, double-blind, placebo-controlled trial. Alcohol Clin. Exp. Res. 34: 1849-57.
8. Del Re AC, Gordon AJ, Lembke A, Harris AH. 2013. Prescription of topiramate to treat alcohol use disorders in the Veterans Health Administration, Addiction Science and Clini- cal Practice. 8
9. Spanagel R, Zieglgansberger W. (1997). Anti-craving compounds for ethanol: New pharmacological tools to study addictive processes Trends in Pharmacological Sci- ences 18: 54-59.
10. Bouza C, Maagro A, Muñoz A, Amate JM. (2004). Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: A systematic review Addiction 99: 811-828.
