The Impact of Alcohol on The Brain – Neurobiology of Dependence and Alcohol Related Brain Damage

ETIOPATHOGENESIS OF ALCOHOL DEPENDENCE

The etiopathogenesis of alcoholism involves a complex interplay between biological, psychological and socio-environmental factors. However, one of the strongest predictors is the genetic disposition of an individual, with heritability estimated to range between 50% and 64% of cases.[2]

Variation in genes encoding enzymes involved in the metabolism of alcohol dehydrogenase or aldehyde dehydrogenase has been shown to influence the risk of alcohol dependence. [3]

Young males who have experienced a traumatic event can develop low
levels of MAO‑A expression (an enzyme that breaks down serotonin), and this decrease in MAO‑A levels correlates with an increase in antisocial behaviour, which is a risk factor for alcohol dependence.

Alcohol (ethanol) is liposoluble and can cross the blood-brain barrier where it has been shown to interact directly, and indirectly, with a wide range of neurotransmitters and hormones such as γ-aminobutyric acid (GABA), glutamate, dopamine, opioids, epinephrine, norepinephrine, serotonin, acetylcholine, cannabinoids, corticotropin-releasing factor (CRF), and neuropeptide Y.

Alcohol dependence is characterised by deficits in the physiological dysregulation of motivation and reward systems, such as those in the limbic system, hippocampus, amygdala, caudate nucleus, frontal lobe and nucleus accumbens.

You can read more about the neurobiological basis of addiction in a previous post we covered. It covers the process of the progression from habit to compulsion.

The dysfunction of these systems is responsible for acute alcohol intoxication, alcohol dependence, and withdrawal syndrome.

NEUROBIOLOGY OF ALCOHOL DEPENDENCE

Alcohol has both positive and negative reinforcing actions in the brain.

Dopamine:

The positive reinforcing action of alcohol comes from the activation of the dopaminergic reward pathway in the limbic system. Dopamine is a neuromodulating compound that is released in the ventral tegmental area (VTA) and projects to the nucleus accumbens (NA) where it is acutely involved in motivation and reinforcement behaviours.

Dopamine is the major neurotransmitter involved as part of the mesolimbic system projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NA)

Studies have shown that there is a dose-response relationship between alcohol intake and dopamine release.[4], [5]

This ethanol-induced dopamine release is directly and indirectly promoted through alcohol’s interaction with GABAergic neurons and opioid receptors in the nucleus accumbens. [6], [7], [8]

GABA:

GABA is the brain’s major inhibitory neurotransmitter. Alcohol acts presynaptically at the GABA neuron,, increasing GABA release and postsynaptically enhancing GABA receptor action.

Baclofen, a GABA-B agonist, has shown to be very effective in the treatment of alcohol dependence, and, in particular, extremely efficacious in effortlessly reducing the motivation to drink. [9]

Glutamate: [10]

Glutamate is the brain’s major excitatory neurotransmitter system. Alcohol reduces glutamate levels in the nucleus accumbens and suppresses glutamate-mediated signal transmission in the central nucleus of the amygdala.

Alcohol alters NMDA and metabotropic MGlu5 receptors thus interfering with glutamate transmission.

Acamprosate used in the treatment of alcohol dependence has demonstrated that its mechanism of action is through its inhibition of the NMDA receptor.

Topiramate is another agent used in alcohol dependence which is not only effective in reducing alcohol craving but also reducing symptoms of depression and anxiety.

Topiramate is known to modulate the dopamine reward pathways of the brain by acting as an antagonist of excitatory glutamate receptors at a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptors and inhibiting dopamine release within the mesocorticolimbic system while enhancing inhibitory GABA (by binding to a site of the GABA-A receptor). [Paparrigopoulos T et al., 2011]

Alcohol reduces glutamate excitotoxicity (VTA); enhances GABA inhibitory activity (VTA) and enhances dopamine release from the VTA to NA by disinhibiting GABA via endogenous opioids. The release of dopamine mediates alcohol’s pleasurable and reinforcing actions.

Serotonin: [10]

There is evidence of a link between serotonin deficiency, impulsivity and drinking behaviour which may explain the role of SSRIs in suppressing alcohol reinforced behaviour in some alcohol-dependent patients.

On the other hand, SSRIs are associated with new-onset alcohol dependence in some patients. The differential effects highlight the presence of different subtypes in alcohol dependence.

Opioid Systems: [10]

Opioid systems involving endogenous opioids (endorphins, enkephalins and dynorphins) influence drinking behaviour via interaction with the mesolimbic system.

Naltrexone is an opiate-receptor antagonist and has been shown to limit cravings by reducing the positive reinforcement effect of alcohol consumption.

Moreover, naltrexone has been shown to reduce alcohol priming (i.e. increased desire to drink), which may reduce the likelihood of heavy drinking. [11]

Acetaldehyde: [10]

The primary breakdown product of ethanol is acetaldehyde, which is produced through a series of oxidative metabolic reactions. [12]

Acetaldehyde is a highly reactive compound that reacts with several catecholamines (i.e. dopamine and serotonin) in the brain.

These reactions produce psychoactive alkaloids such as salsolinol and tetrahydropapaveroline.

These alkaloid compounds have been suggested to be responsible for the physiological effects of alcohol as well as the manifestation of the behavioural aspects of alcohol-related disorders.

Disulfiram is is a drug that inhibits the enzyme aldehyde dehydrogenase and is used in the treatment of alcohol dependence. The accumulation of acetaldehyde is known to cause unpleasant side effects such as vomiting, headaches, and anxiety after the consumption of alcohol.

Disulfiram administration helps patients learn non-drinking behaviours and the ability to exercise self-control. Most individuals cease alcohol use after the administration of disulfiram due to the strong expectancy of negative consequences.

Other systems: [10]

• Norepinephrine
• Orexin
• Vasopressin
• Neuropeptide S and Y
• Corticotrophin-Releasing Factor (CRF)

MECHANISMS OF ALCOHOL RELATED BRAIN INVOLVEMENT [3]

Ethanol-specific effects

• Toxic metabolites of ethanol, such as acetaldehyde and fatty acid ethyl esters, can disorder phospholipids, interrupt mitochondrial function, and induce neuronal damage.
• Oxidative stress via the generation of reactive oxygen species (such as nitric oxide and lipid peroxidation products) that accumulate and cause DNA damage, inhibition of gene expression, and neuronal death
• Reduction in Brain-Derived Neurotrophic Factor (BDNF)  a neurotrophin necessary for neuronal survival, growth, and differentiation.
• Excitotoxic activity during alcohol withdrawal mediated via dysregulation of glutamate release and uptake, and stimulation of NMDA receptors

Thiamine deficiency
Thiamine deficiency leads to low levels of active thiamine (thiamine pyrophosphate) in the brain, which impairs several biochemical pathways in the brain:

• Carbohydrate metabolism – For energy production
• Lipid metabolism – For the production and maintenance of myelin
• Amino acid metabolism – For the production of GABA and glutamate

Liver dysfunction

• Elevated ammonia – Affects cerebral blood flow and astrocytic function
• Elevated manganese – Affects the dopaminergic system, enhances oxidative stress, and induces neurotoxicity

Synergistic effects

• Neuroinflammation (learn more about neuroinflammation here)

ALCOHOL RELATED BRAIN INVOLVEMENT

The following are key neurofunctional abnormalities with key areas of the brain involved. [3], [13], [14]

1. Executive function, impaired judgement, impulsivity, blunted affect, distractibility, reduced motivation, and disinhibition – Frontal lobes
2. Memory dysfunction – Mammillary bodies, hippocampus, thalamus, hypothalamus and caudate nucleus
3. Visuospatial abilities – Corpus callosum
4. Upper and lower limb control – Corpus callosum and cerebellum
5. Oculomotor control – Pons and cerebellum

WERNICKE-KORSAKOFF'S SYNDROME (WKS)

Wernicke’s Encephalopathy (WE) –

Wernicke’s encephalopathy is an acute, yet potentially reversible, neuropsychiatric disorder caused by a deficiency (or depletion) in thiamine (thiamine pyrophosphate) caused by chronic alcohol use. Other causes include gastric bypass surgery, gastric and colon cancer, hyperemesis gravidarum, long-term parenteral feeding, and poor nutrition.

Genetic susceptibility linked to thiamine transporter genes may be involved in the development of WKS in vulnerable patients.

Wernicke’s encephalopathy is a medical emergency. Untreated, it leads to death in up to 20% of cases.

Thiamine deficiency in alcohol dependence occurs because of poor absorption of thiamine from the GI tract, impaired thiamine storage and reduced thiamine phosphorylation in the brain, reducing the amount of active thiamine in the brain.

Clinical Features:

Triad consists of:

1. Oculomotor abnormalities – Lateral rectus palsy, nystagmus, ophthalmoplegia
2. Cerebellar dysfunction – Ataxia
3. Altered mental state – Confusion

Clinical Pearl –  Only 20% of patients may show the full triad in clinical practice.

The European Federation of Neurological Societies (EFNS) recommends a presence of two of the following four signs as evidence of Wernicke’s encephalopathy [15] –

1. Dietary deficiency
2. Oculomotor abnormality
3. Mild memory impairment
4. Altered mental status

Treatment of acute WE [15], [16] –

• Thiamine 500 mg IV TDS for 2-3 days and 250 mg daily for next 3-5 days
• Thiamine 100 mg PO TDS for rest of hospital stay
• Multivitamins
• Replace lost Mg
• Replace fluid and electrolyte losses

Clinicians suspecting Wernicke’s encephalopathy in a patient should treat it as an emergency and provide optimum intravenous treatment in order to avoid permanent brain damage. (BNF)

Prophylactic treatment for patients at risk of WE – Thiamine 200-300 mg IM daily for 3-5 days.

Korsakoff’s Syndrome:

Undiagnosed and untreated, WE can lead to Korsakoff’s syndrome in 80% of cases.

Clinical features: 

First described by Victor (1971)

An abnormal mental state in which memory and learning are affected out of all proportion to other cognitive functions in an otherwise alert and responsive patient

• Anterograde amnesia (impaired ability to acquire new episodic memories)
• Confabulation
• Retrograde amnesia
• Lack of insight
• Disorientation in time and place
• Executive dysfunction
• Sequelae of WE

MRI findings in WKS-

• Mamillary body atrophy
• Neuronal loss in the anterior principal and mediodorsal nuclei of the thalamus and the basal forebrain

The most obvious neuroradiological sign of acute WE, regardless of etiology, is bilateral hyperintensity on late-echo MRI, generally occurring in gray matter tissue of the mammillary bodies, anterior and medial nuclei of the thalamus, periventricular gray matter, inferior and superior colliculi. [17]

Image from Case courtesy of Dr Lee-Anne Slater, Radiopaedia.org. From the case rID: 12151

Wernicke’s Encephalopathy – High-intensity signal around periventricular areas.

NEUROPSYCHIATRIC COMORBIDITIES

Psychiatric disorders are commonly associated with alcoholism, and the compounded dysfunction of their comorbidity is a critical element in the diagnosis and treatment of these patients.

There are four main hypotheses in dual diagnosis cases:

A national survey (SAMHSA) in 2014 showed that of the 20 million American adults with a substance use disorder, almost 8 million also suffered from a mental illness [18].

Mood and anxiety disorders are common alcohol abuse disorders with one large epidemiological study showing that over 30% of individuals with alcohol dependency had a co-morbid mood disorder [19].

In this study, it was shown that alcohol dependency comes with a 4-times increase in the risk of developing a major depressive disorder.

Conversely, there are also high rates of alcohol-related disorders in psychiatric patients, particularly in those with bipolar disorder and depression when compared to the general population [19], [20].

Patients with schizophrenia are also highly likely to suffer from alcohol abuse due to their tendency to devalue negative consequences and overvalue rewards [21].

A large retrospective 2018 French cohort study found that alcohol use disorders were the strongest modifiable risk factor for dementia onset, with an adjusted hazard ratio of 3·34 (95% CI 3·28–3·41) for women and 3·36 (3·31–3·41) for men. [22]

The study found that alcohol use disorders were associated with all types of dementia even after controlling for other confounding factors.

CONCLUSION

Excessive alcohol consumption is associated with structural changes in certain brain areas and functional changes to neurotransmitter pathways that cause impairments to cognition and behaviour. The effects, however, differ from person to person.

Exciting developments are happening in the world of addiction that will allow clinicians and researchers to develop targeted therapies that may be able to prevent addiction and alcohol-related brain damage in dependent individuals.