Written by Quek Ten Cheer
Edited by Sasinthiran
Alcohol addiction is a serious societal issue that can lead to many domestic and social problems. One way to prevent this issue from becoming worse is to understand more about how alcohol, as a drug, causes these problems. In this article, we aim to inform readers on the biological effects of alcohol, especially on the brain, and how addiction is currently being treated medically.
Alcohol and crime
Alcohol has been implicated in between 57% and 85% of violent crimes1. In addition, many suicides are committed under the influence of alcohol2. The most likely mode of action for alcohol in stimulating aggression is its general disinhibiting effects on behaviour. Alcohol silences higher cortical areas responsible for impulse control, often leading to behaviour that is normally actively suppressed, including aggression.
What is alcohol?
Alcohol is a psychotropic drug, which means that it is a drug that affects our mental state. This places alcohol (commonly referred to as ethanol in scientific literature) in the same category as:
- Cannabinoids (the active material in cannabis, or marijuana);
- Nicotine (one of the active psychotropic agents in cigarettes and cigars);
- Psychostimulants, much stronger drugs which include cocaine, MDMA (commonly known as ecstasy), and methamphetamine (you might know it as the blue ‘meth’ from Breaking Bad);
- Opiates, morphine-like drugs such as heroin (diacetyl morphine).3,4
In addition, alcohol is a biphasic drug5; small amounts act as a stimulant by reducing inhibition and producing mild euphoria. Higher doses depress the central nervous system (CNS) that will initially promote relaxation but lead to the person experiencing effects such as ataxia (uncoordinated movement), sedation and general ‘drunkenness’.
Fun fact: Asian Flush
Some of us get the ‘Asian flush’, i.e. our faces become reddish from drinking (because the body is unable to quickly metabolize acetaldehyde, a by-product of alcohol metabolism). (Acetaldehyde is the main culprit behind headaches, nausea, and hangovers).
In fact, the reaction that breaks down acetaldehyde, by means of the enzyme aldehyde dehydrogenase, is faster in alcoholics than in non-alcoholics.6
What makes a person addicted to alcohol? The 5th edition of the Diagnostic and Diagnostic and Statistical Manual of Mental Disorders (DSM-V), recognises excessive use of alcohol as a disorder in which patients are diagnosed with the substance use disorder when they display at least 2 of the following 11 symptoms within a 12 month period:
- Consuming more substance than originally intended
- Worrying about stopping or consistently failed efforts to control one’s use
- Spending a large amount of time using the substance, or doing whatever is needed to obtain them
- Use of the substance results in failure to “fulfil major role obligations”
- “Craving” the substance
- Continuing the use of a substance despite health problems caused or worsened by it
- Continuing the use of a substance despite its having negative effects in relationships with others
- Repeated use of a substance in a dangerous situation (e.g. when driving a car)
- Giving up or reducing activities in a person’s life because of the substance use
- Building up a tolerance to the alcohol or drug. Tolerance is defined by the DSM-V as “either needing to use noticeably larger amounts over time to get the desired effect or noticing less of an effect over time after repeated use of the same amount.”
- Experiencing withdrawal symptoms after stopping use. Withdrawal symptoms typically include, according to the DSM-V: “anxiety, irritability, fatigue, nausea/vomiting, hand tremor or seizure in the case of alcohol.”
As can be seen from the DSM-V definition of alcohol use disorder, the interpretation of an individual’s use of alcohol as being excessive and leading to dysfunction is subjective and must be considered together with environmental and contextual factors.
However, alcohol addiction is also largely a problem that needs to be treated by addressing the environmental factors in addition to its targeted pharmacological treatment; prescribed medicines alone cannot fully treat the condition.
There is a plethora of literature on many illicit drugs of abuse, in particular cocaine. They demonstrate the pharmacological basis by which people become addicted to these drugs, in hopes of deriving better pharmacological treatment which targets, mainly, the addiction pathways in the brain.
Let’s talk about the brain
Firstly, if we want to know anything about alcohol addiction, we need to start with the very-important mesolimbic pathway, commonly called the ‘reward pathway’ for its role in addiction and associated disorders. You can recall this term and its position in the brain by the fact that ‘meso’ means ‘middle’ in Greek, and it is located in the middle of the brain. Thus ‘mesolimbic’ also means the midbrain, or ‘middle brain’.
The mesolimbic pathway, highlighted in the opaque blue in the above figure7, connects the ventral tegmental area (VTA) to the nucleus accumbens (NAC). It is also referred to as a dopaminergic pathway (abbreviated DAergic pathway) because it transmits the neurotransmitter dopamine throughout the two areas.8 Don’t underestimate its small size! It is the most significant neural pathway in the brain within which changes occur in all known forms of addiction. It is widely studied in the reward circuitry underlying drug abuse, depression, addiction, as well as conditioning and studies on human behaviour.
The brain is addicted to pleasure and positive effects; more specifically, it craves any activity which leads to the activation of dopaminergic pathways that trigger the brain’s reward response with the release of the neurotransmitter dopamine 9. Research shows that addictive substances such as alcohol are in fact addictive primarily because they activate such pathways leading to a reward response, leaving the brain craving for more 10. In other words, the more a particular behaviour, such as taking alcohol, triggers the reward centers of the brain, the more the brain seeks out such behaviour through learned operant conditioning by positive reinforcement. This then increases the occurrence of that behaviour in the future (thus, addiction).
A 2003 study done by Boileau et al. have found that the consumption of alcohol stimulates the release of dopamine in the nucleus accumbens12. Dopamine (commonly abbreviated as DA in literature) was synthesised over 100 years ago (in 1910), but was recognised to be a neurotransmitter many decades later, in the 1950s. In the brain, dopamine is produced in hypothalamic neurons as well as neurons of the VTA and substantia nigra.13
After secretion of DA into the synapse, the intact molecule is reabsorbed into the neurons by a specific transporter, the dopamine transporter (DAT). They are then metabolised within cells by monoamine oxidase (MAO) or catecholamine O-methyl transferase (COMT); both enzymes convert dopamine into inactive products.
Compounds that inhibit DAT, such as cocaine (meaning the effect of dopamine is prolonged in the synapse as its concentration remains elevated), cause mood elevation and addiction.
Compounds that inhibit MAO (meaning DA does not get broken down after being re-uptaken) are effective antidepressants, which includes selective serotonin reuptake inhibitors (SSRIs), such as Prozac (you might know it as ‘fluoxetine’ or ‘fluoxetine HCl’ if you’ve ever had hypochondriac tendencies).
Neurotransmitters/neuropeptides that influence alcohol consumption
In alcohol addiction, there are several neurotransmitters and neuropeptides in the brain that influence alcohol consumption. These include Glutamate, GABA (gamma-aminobutyric acid), nACHR/glycine, DA/5-HT, Cannabinoids, Opioids, and CRF/NPY.11
Potassium channels and GABAA receptors in the VTA
Among the potential means by which alcohol might influence the firing rate of dopaminergic neurons in the brain, the best studied are the actions of ethanol on potassium channels and GABAA receptors in the VTA.
Alcohol functions as an agonist of GABAA receptors and its binding to these receptors leads to the inhibition of the post-synaptic neurons. Alcohol, by binding to GABAA receptors on VTA GABAergic interneurons, may disinhibit (activate) VTA dopaminergic neurons that project to the NAc (nucleus accumbens) which is involved in producing a feeling of pleasure and mood elevation (Nestler, 2005)14.
Interestingly, autopsies of alcoholics’ brains have revealed that they were in a hypodopaminergic state, which explains why alcoholics would continue to seek out more alcohol to achieve the sensation of pleasure and mood elevation they have learnt to associate with alcohol consumption.
Pharmacology of alcohol on the brain
Alcohol is generally viewed as being an unspecific pharmacological agent, but based on recent studies it has been shown to act by disrupting distinct receptor or effector proteins via direct or indirect interactions. There is a widespread plethora of literature on the abuse of psychostimulants, especially cocaine. (There is, however, scarce publications on abuse of alcohol.)
At concentrations in the 5-20mM range, which is the legal intoxication range for driving in many countries, alcohol directly interferes with the functions of several ion channels and receptors.11
Recent molecular pharmacology studies demonstrate that alcohol has a few primary targets, which include NMDA, GABAA, 5-HT3, nAChR, as well as L-type Ca2+ channels and GIRK, where concentrations as low as 1mM produce alterations in the functions of these receptors and ion channels. Some of these are outlined below:
NMDA receptors are commonly associated with excitatory glutamatergic activity and in the formation of Long Term Potentiation (LTP) which is essential for memory formation. Disruption of this receptor function by alcohol explains why many would find it difficult to remember the events of a night out when heavily intoxicated15– also known as ‘blackout’.
More inhibitory GABAA receptor activity
Moreover, alcohol has been found to stimulate inhibitory GABAA receptor activity by serving as an agonist in the hippocampus, an area of the brain associated with memory formation, contributing to this brief amnesic episode16.
Alcoholic activation of inhibitory GABAA activity of neurons projecting to higher areas of the cortex brings about reduced inhibitions and anxieties and facilitates better social interactions while reducing impulse control.
In fact, recovering alcohol addicts often experience life-threatening seizure episodes as a withdrawal symptom due to a rebound effect whereby inhibitory GABAA receptors become hypoactive in the absence of alcohol.
Alcohol also functions as an endorphin, mimicking the effects of opiate drugs and producing an endorphin ‘high’ associated with the use of such drugs.
More inhibitory neuromodulator activity
Alcohol has also been found to increase the activity of inhibitory neuromodulators such as adenosine which leads to sedative effects and a reduced state of awareness.
Treatment of alcohol addiction
It is estimated that 7.9% of people 12 years or older in the U.S. require help for alcoholism, more than twice the percentage of the population estimated to require treatment for the abuse of all illicit drugs collectively.
Alcohol use has been linked to diseases and ailments such as malnutrition (due to the ‘empty calories’ of alcohol) and in particular fetal alcohol syndrome (which causes developmental and physical abnormalities in the offspring of mothers who consume alcohol during pregnancy).
Alcohol abuse has been linked to domestic abuse, sexual assault, and can destroy families.
Treatment of alcohol addiction is largely based on psychological and psychiatric help, as compared to pharmacologically-based treatment.
Alcohol addiction requires a multi-pronged approach to treatment. Drugs alone show little effect insofar as treatment is concerned; environmental factors need to be addressed when treating alcohol addiction. Treatment involves the facilitation of abstinence and the prevention of relapse.
Pharmacologic treatment is often used to reduce withdrawal symptoms, but thus far has not been effective in preventing relapse. It is a theoretical possibility, however, that medications which block the reinforcing effects of drugs or drug-induced plasticity might reduce drug craving and the likelihood of relapse. Such medications can be effective if they can act without interfering with the body’s responsiveness to natural rewards (e.g. anhedonia, when the abuser suddenly finds a drastic disinterest in normal daily activities). Currently, no reward-reducing drug treatment has yet been established for clinical use.
- Cacioppo J., Freberg L., 2013. Discovering Psychology: The Science of Mind, Briefer Version. Wadsworth, Cengage Learning, Chapter 11, pp. 600.
- Sher L. (2006). Alcohol Consumption and Suicide. QJM, 99(1):57-61.
- Nestler, E. J.; Hyman S. E.; Malenka R. C. Molecular Neuropharmacology: A foundation for clinical neuroscience (2nd) McGraw-Hill. pp. 364-388
- Pierce, C.R., Kumaresan V., 2006. The mesolimbic dopamine system: The final common pathway for the reinforcing effect of drugs of abuse? Neuroscience and behavioural reviews, 30, Issue 2, pp. 215-238.
- Glossary: Drugs and Alcohol. (n.d.). Retrieved July 16, 2016, from https://www.newscientist.com/article/dn9923-glossary-drugs-and-alcohol/
- Campbell, M. K., Farrell, S. O. (2009,2012). Biochemistry. Brooks/Cole Cengage Learning. pp. 689.
- Mesolimbic pathway. (2015) [Image from https://en.wikipedia.org/wiki/Mesolimbic_pathway]
- “Mesocorticolimbic Dopaminergic Neurons.” Neuropsychopharmacology: The Fifth Generation of Progress. Retrieved from http://www.acnp.org/g4/gn401000025/ch025.html
- Insel, T. R., 2003. Is Social Attachment an Addictive Disorder?. Physiology and Behavior, 79(3), pp. 351-357.
- Koob, G. F. & Moal, M. L., 1997. Drug Abuse: Hedonic Homeostatic Dysregulation. Science, Volume 278, pp. 52-58
- Vengeliene V.; Bilbao A.; Molander A.; Spanagel R. Neuropharmacology of alcohol addiction. British Journal of Pharmacology (2008) 154, 299-315.
- Boileau I. et. al, Alcohol promotes dopamine release in the human nucleus accumbens. Synapse 49:226-231 (2003). Retrieved from http://onlinelibrary.wiley.com.libproxy1.nus.edu.sg/doi/10.1002/syn.10226/epdf
- W. Pfaff (ed.), Neuroscience in the 21st Century, DOI 10.1007/978-1-4614-1997-6_51, # Springer Science+Business Media, LLC 2013
- Nestler, E. J. Is there a common molecular pathway for addiction? Nature Neuroscience 8, 1445 – 1449, 2005
- Lovinger, D. M.; White, G.; Weight, F. F. NMDA receptor-mediated synaptic excitation selectively inhibited by ethanol in hippocampal slice from adult rat. Journal of Neuroscience 10:1372. 1379, 1990.
- Weiner, J. L.; Zhang, L.; Carlen, P. L. Potentiation of GABAA-mediated synaptic current by ethanol in hippocampal CA1 neurons: Possible role of protein kinase C. Journal of Pharmacology and Experimental Therapeutics 268:1388. 1395, 1994