Do you dare to "buy drunk"?

Introduction Alcohol hangover (AH) is defined as a series of unpleasant physiological and pathological reactions experienced after a large amount of alcohol intake.

This reaction is common within a few hours after drinking alcohol (up to 10h), especially when the plasma alcohol concentration BAC>0.
08%, it can last up to 24 hours.

At present, more than 47 symptoms are considered to be related to it.
The most common ones include fatigue, headache, nausea, and attention deficit.

Part of the symptoms can be seen in the withdrawal period of alcohol dependent persons.
At this time, the symptoms are often more severe and last longer, and may be accompanied by severe anxiety, tension, negative states, sweating, and seizures.

AH can also cause severe executive function (attention, memory, psychomotor skills, etc.
) obstacles and daily skills (such as driving) obstacles, resulting in a decline in the overall work performance of individuals, resulting in increased accidents, increased absenteeism, and decreased productivity (further Affect social efficiency) and so on.

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Clinical manifestations and influencing factors At present, the physiological and neurological mechanisms related to AH are unknown.
The changes in related neurotransmitters can appear before clinical symptoms and help reflect the severity of symptoms.

A variety of factors are thought to aggravate AH (Table 1), but only some are thought to be related to the severity of AH.

In addition, immune factors can reduce the inhibitory effect of prostaglandin synthesis, which may also be related to the severity of AH.

Dehydration and sleep disorders are the most common symptoms of AH and are related to changes in multiple hormones (VPA, cortisol, electrolytes and glucose concentrations).

Table 1 AH-related performance Some studies suggest that urine ethanol concentration is related to related symptoms of HA-sensitive people, including nausea, attention disorder, sleepiness, fatigue, apathy, sweating, stomach pain, thirst, rapid heartbeat, anxiety and sleep problems, etc.
.Glyoxylate, ethyl sulfate, and non-oxidative secondary metabolites (>0.
1%) of ethanol metabolism are related to urine ethanol concentration, but not to the overall degree of HA.

Other studies have found that in people who are sensitive or insensitive to HA, the alcohol content in the breath is related to the severity of HA.

Therefore, the ethanol clearance rate may be related to the reduced severity of HA.

 The ingredients in other alcoholic beverages (especially congeners) are considered to be related to the severity of HA (Table 2).

Congeners refer to substances that can cause HA-related symptoms in the process of distillation or fermentation to produce ethanol, including amines, amides, acetone, acetaldehyde, polyphenols, methanol, histamine, fusel oil, esters and Tannins etc.

High-concentration congeners are found in red wine, black wine (brandy), and low-concentration sake (vodka).

Methanol is the most important homologue.
Alcohol dehydrogenase (ADH) metabolizes methanol at a slower rate than ethanol to form formaldehyde and formic acid, both of which are highly toxic and may cause hangovers.

Table 2 The homologues that cause the severity of HA (commonly found in the chemical components added to alcoholic beverages, and in the process of ethanol distillation or fermentation) HA-related molecular chemistry and neurochemical factors 1.
Ethanol and its metabolites (acetaldehyde) Alcohol is first metabolized by ADH to acetaldehyde and then acetaldehyde dehydrogenase (ALDH) to acetic acid.

Acetic acid is the precursor of acetyl-CoA (CoA), which is then converted into CO2 and water in the krebs cycle.

Acetaldehyde is very toxic, but it is quickly metabolized (although its clearance rate in the brain is unknown).

In the East Asian population, about 36% of patients developed flushing reactions after drinking a small amount of alcohol, manifested as redness of the face, neck and shoulders, nausea, tachycardia and headache (also manifested in HA), which is mainly due to the lack of mitochondria in this group of people The ALDH gene causes the accumulation of acetaldehyde to increase the concentration; and a small number of people in the United States, Australia, Ireland and the United Kingdom also have similar symptoms, but it is not caused by the accumulation of high concentrations of acetaldehyde, but is related to the amines that act on blood vessels (including Histamine, catecholamine) changes.

Previous studies on the correlation between acetaldehyde and HA have different conclusions.

Some studies believe that serum and urine acetaldehyde concentration changes little after acute ethanol intake, while serum acetic acid concentration can increase at least 6 hours after ethanol intake (indicating that acetic acid is metabolized in the brain is increased), suggesting acetic acid As one of the sources of brain energy, another study found that the concentration of acetic acid in the blood is related to headaches.

Figure 1 Ethanol-mediated endoplasmic reticulum (ER) stress and organ damage (Ji C.
Mechanisms of alcohol-induced endoplasmic reticulum stress and organ injuries[J].
Biochemistry research international, 2012.
) ADH: alcohol dehydrogenase; ALDH: acetaldehyde dehydrogenase; CYP2E1: cytochrome P450 2E1; ROS: reactive oxidative stress; GSH: glutathione; BHMT: betaine-homocysteine ​​methyltransferase; MS: methionine synthase ; Hcy, homocysteine; SAM: S-adenosylmethionine, SAH: S-adenosyl homocysteine; TCA: tricarboxylic acid; UPR: unfolded protein response; GRP78: glucose regulation Protein 78; IRE1: inositol requires enzymes; ATF6: activating transcription factor 6; PERK: protein kinase dsRNA-dependent ER kinase; CHOP: C / EBP homologous protein; JNK, c-jun-N-terminal kinase; NFB, Nuclear factor B; SREBP: sterol regulatory element binding protein; Xbp-1: X box binding protein 1; GADD34: growth arrest and DNA damage-inducing protein.

 2.
Acute ethanol intake of neurotransmitters and their receptors can affect many neurotransmitter systems, including GABA, glutamate, dopamine, 5-HT and endogenous catecholamine systems.

The irritating toxicity caused by initial alcohol intake is related to dopamine and brain-derived nutritional factor (BDNF), which promote the activation of TrkB receptors and downstream signaling pathways.

The balance between inhibitory GABAergic neurotransmitter and excitatory glutamate neurotransmitter will also change, including reducing GABA and GABAR insensitivity, and increasing Glu and GluR inhibitory properties.

Animal experiments found that the level of extracellular glutamate in the nucleus accumbens decreased, while the levels of glutamate and GABA in other parts increased, which may be related to the withdrawal response.

The toxicity caused by the increased release of glutamate in the striatum plays an important role in the initial stage of abstinence after chronic alcohol intake and after "popping".

 3.
Inflammatory reaction Ethanol can affect the inflammatory reaction process, including the periphery and the center, and there is a complex connection between the two.

Ethanol's response to antigens can inhibit the expression of cytokines, resulting in a weakened response to bacteria and other exogenous substances.

Toll-like receptors in peripheral monocytes and central microglia can be activated by ethanol (causing NFκB activation), and can also cause ethanol-mediated intestinal dystrophy (endotoxin leaked from the intestine, causing glial Cells and neuronal cells induce inflammation and oxidative stress), thereby causing a variety of symptoms, the severity of which is lower than that of chronic alcoholism and withdrawal.

During AH, cytokines in blood, monocytes, and saliva increase, and changes in different cytokines are related to different symptoms.

In healthy non-drinkers, IL8 increased after 36 hours of acute alcohol intake.
When alcoholism and BAC reached 0.
12%, IL-1Ra increased and MCP-1 decreased.
At 12 hours BAC=0, only MCP -1 increased.

When the AH state was caused 13 hours after ingestion of 1.
5g/kg of ethanol, plant lectins stimulated monocytes to increase the secretion of IL-10, IL-12 and IFN-γ, but II-1b, IL-4, IL- 6 and TNFα did not change significantly before drinking, and the concentration of IFN-γ and IL-12 was related to the AH severity score.

In addition, 9 hours after ethanol intake, IL2, IL-4, IL5, IL-6, IL-10, IFNγ and TNFα in saliva increased, while only IL-4 and IL-6 in urine increased.

The level of cytokines in urine is less obvious than that in saliva, and BAC is generally not detected until 9 hours after a hangover.

There was no difference in the degree of cytokine changes between alcohol-sensitive and insensitive people during a hangover, but a comparison of immune function auestionnarire showed that the immune function score of people with hangovers was higher than that of people without hangovers (the former's immune function).
worse).

However, the relationship between cytokine changes and individual immune response is not clear.

Glial cells play an important role in alcohol-mediated neuroinflammatory response.

Microglia are the initial mediator of the innate immune system in the brain.
Previous studies have found that the number of microglia increases after drinking alcohol, but they cannot be eliminated by immunosuppressive agents or their related mediators, suggesting that microglia Plasma cells do not express cytokines during the acute phase of hangover.

The central nervous mediators related to hangover still need to be further studied.

At present, the direct evidence for the inflammatory response after AH is 400 mg of toluenesulfonic acid (NSAID), which can reduce the symptoms and scores of AH, and reduce the levels of plasma PGE2 and thrombus B.

 4.
Mitochondrial dysfunction.
Ethanol can damage mitochondrial DNA, especially in the liver.

However, because brain cells rely solely on mitochondria for aerobic metabolism, mild mitochondrial dysfunction can cause free radical production and oxidative stress disorders in related brain functional areas (especially the cerebellum, prefrontal lobe and hippocampus), affecting synaptic remodeling , Causing related symptoms.

 5.
Auditory evoked response Brainstem auditory evoked latency is the response to auditory stimuli, reflecting the activity of the auditory nerve, cochlear nucleus, upper olive and brainstem hypothalamus.

The study found that the hearing threshold of AH decreased.

 6.
MRS advanced imaging techniques such as MRS, fMRI, electroencephalogram, magnetoencephalogram, PET and other examinations help to detect abnormal brain structure and function.

The fMRI study found that when BAC=0.
08% after drinking, the cerebral blood flow of the thalamus increased; the orbital frontal lobe, dorsolateral temporal lobe and hippocampus were activated only 8 hours after drinking.

The psychomotor vigilance task can compensate for the structural functions of the prefrontal and temporal lobes, which helps explain the further relationship between the two.

Summary AH is a multifactorial event, involving a variety of biochemical, neurochemical events and genetic related factors.

The current calculation of the exact time when the hangover begins is still unclear.

Through a variety of experiments and animal studies, pathological changes related to the hangover state have been identified, including inflammatory response, neurotransmitter, receptor changes, mitochondrial dysfunction, and alcohol metabolites.

Different factors may be related to the specific symptoms of AH, and further research is needed to clarify.

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