Alcohol Use Disorder (AUD)
AUD stands out among the other SUDs discussed, as its diagnosis can be based on criteria related to tolerance (which excludes cross-tolerance due to appropriately used prescription sedatives) and withdrawal. This section discusses some of the cellular mechanisms of tolerance and withdrawal syndrome.
AUD Diagnosis
According to the DSM-5-TR, diagnosis of AUD requires meeting at least two of eleven criteria, indicating a problematic drinking pattern resulting in significant impairment or distress.
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Some of these criteria are categorized and summarized here.
Pharmacological Criteria
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Tolerance (more alcohol is needed to achieve intoxication or desired effects)
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Withdrawal syndrome (may include tremor, anxiety, high blood pressure, rapid heart rate, perspiration, and nausea/vomiting; in more severe cases, seizures, delirium tremons, or death may occur)
Impaired Control Over Use
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Drinking more than intended
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Craving/strong desire to drink alcohol
Social Impairment
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Alcohol use continues despite social or interpersonal problems caused or exacerbated by alcohol
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Giving up or reducing social, occupational, or recreational activities because of alcohol use.
Risky Use
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Continuing alcohol use despite knowledge of having physical or psychological consequences of alcohol.
The Pharmacological Effects of Alcohol
When orally ingested, alcohol (ethanol) is absorbed primarily through the gastrointestinal tract, with approximately 90% absorbed in the small intestine. Alcohol is a small, water-soluble molecule that travels through the bloodstream and readily crosses the placental and blood-brain barriers. Various factors, including food in the stomach, genetic predispositions, and individual physiological differences, influence the bloodstream's alcohol levels. A blood-alcohol concentration (BAC) 0.02 is required to produce measurable behavioral effects (Meyer et al., 2023).
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Once in the blood, alcohol readily diffuses across cell membranes, disrupting lipid composition and interacting with polar heads, disturbing relationships between proteins and cell membranes, including receptors (Abrahao et al., 2017; Meyer et al., 2023). Ethanol also indirectly interacts with intracellular signaling proteins, such as protein kinase C and adenylate cyclase, growth factors, transcription factors, and epigenetic modification proteins (Abrahao et al., 2017; Meyer et al., 2023).
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Alcohol acts as a CNS depressant in a dose-dependent manner. At low doses, mild mood elevation and relaxation occur, although environmental and expectancy factors also play a role (Meyer et al., 2023). Increased consumption brings increased relaxation, impaired memory, attention, and coordination. At around 0.16-0.30% BAC, these impairments increase in significance, and signs of alcohol overdose (vomiting and loss of consciousness) are evident (Meyer et al., 2023). If the BAC increases after this point, there is a significant risk of coma or death due to CNS depression of vital functions.
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Ethanol is metabolized in the liver by alcohol dehydrogenase, which converts alcohol into the toxic byproduct acetaldehyde. Aldehyde dehydrogenase (ALDH) then converts acetic acid into acetic acid, which is broken down into carbon dioxide, water, and energy (Meyer et al., 2023).
In short, the pharmacological effects of alcohol are widespread and also vary with acute and chronic use. Select mechanisms related to tolerance and withdrawal are discussed.
Tolerance & Withdrawal
Four mechanisms of tolerance occur with repeated ethanol administration:
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Acute Tolerance:
Occurs within a single exposure to alcohol, and refers to subjective and behavioral effects of alcohol being greater when the BAC is increasing, compared to when the BAC is falling, even at the same levels.
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Metabolic Tolerance:
Chronic alcohol use significantly increases the cytochrome P450 family of enzymes in the liver, including ALDH. The increased metabolism of alcohol leads to reduced bioavailability, and overall effect of the drug.
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Behavioral Tolerance:
Rats and humans seem to maintain the ability to learn to adjust their behaviors when allowed to practice under the influence of alcohol (Meyer et al., 2023). Classical conditioning may also contribute to behavioral tolerance.
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Pharmacodynamic Tolerance:
This type of tolerance refers to the many neuroadaptations that occur to compensate for the alcohol exposure and associated cell changes.
Pharmacodynamic Tolerance & Withdrawal
Alcohol exerts its CNS effects through the modulation of various NTs, but two NT systems have long been implicated in AUD withdrawal syndrome (Abrahao et al., 2017). Withdrawal from heavy alcohol consumption triggers an intense abstinence syndrome lasting two to four days, depending on the length and quantity of alcohol consumed. Symptoms typically include tremors, heightened anxiety, elevated blood pressure, rapid heart rate, profuse sweating, accelerated breathing, and nausea/vomiting. Some individuals may experience severe manifestations known as delirium tremens (DTs), characterized by irritability, confusion, agitation, headaches, and in severe cases, seizures and hallucinations. Specific withdrawal symptoms such as unstable blood pressure, depression, anxiety (including panic attacks), and sleep disturbances may persist for weeks or months (Meyer et al., 2023).
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GABA:
Alcohol acts as a positive allosteric modulator in GABA-A receptors. acute alcohol intake induces GABA-mediated hyperpolarization of neurons, resulting in sedation, anxiety reduction, and memory impairment (Meyer et al., 2023; Ngui et al., 2022). Multiple studies have suggested that GABA receptors contribute to the reinforcing effects of alcohol (Meyer et al., 2023). Chronic alcohol consumption induces down-regulation of GABA receptor activity, but not the number of GABA receptors (Meyer et al., 2023). The rebound hyperactivity that occurs in early alcohol withdrawal may contribute to the presence of hyperexcitability, tremors, and seizures (Meyer et al., 2023; Ngui et al., 2022).
Glutamate:
Alcohol's influence on NMDA receptors is particularly significant, as it acts as an antagonist to the excitatory neurotransmitter glutamate. Acutely, this impact extends to learning and memory processes, as alcohol reduces glutamate release in various brain regions, notably the hippocampus. This dual effect—temporary inhibition of NMDA receptors and decreased glutamate release—can result in amnesia for events occurring during intoxication (Meyer et al., 2023). With chronic alcohol consumption, neuroadaptations occur via the up-regulation of glutamate NMDA receptors. During withdrawal, elevated glutamate levels, without the competing presence of alcohol, can induce CNS hyperexcitability, potentially inducing seizures.
It's important to acknowledge that GABAergic neurons often possess glutamate receptors, and GABA itself commonly regulates the release of glutamate. The compensatory mechanisms within each NT system may suggest an interplay between the two (Meyer et al., 2023).
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Other NTs:
Additionally, alcohol amplifies the effects of dopamine and endorphins, contributing to its rewarding and reinforcing properties (Volkow et al., 2019). With chronic alcohol consumption, neuroadaptations occur, leading to decreased levels of endorphins and dopamine, which can manifest as depressive symptoms or dysphoria upon cessation.
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Cross-tolerance with sedatives occurs in cases of alcohol tolerance, as these sedatives act on the the same GABA-A receptors. Healthcare providers may recommend short-term benzodiazepine prescriptions to manage withdrawal symptoms and mitigate seizure risk during supervised alcohol withdrawal for individuals with AUD (Meyer et al., 2023).
Future Directions
The current pharmacotherapies for treating AUD demonstrate moderate effectiveness, with variations in efficacy among individuals potentially linked to their genetic composition (Meyer et al., 2023). Ongoing research is delving into the intricate genetic and epigenetic correlations, as well as exploring direct causal relationships.
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CRF-1 antagonists exhibit promise in reducing alcohol consumption during withdrawal in rodent models (Meyer et al., 2023). Additionally, studies have shown that a selective glucocorticoid receptor antagonist (CORT113176) and a mixed glucocorticoid/progesterone receptor antagonist (mifepristone) can reduce alcohol consumption and craving in individuals with AUD (McGinn et al., 2021; Meyer et al., 2023). Ketamine, an NMDA glutamate receptor antagonist, is also being researched for its potential in treating AUD (Meyer et al., 2023).