Alcohol Flashcards
What is alcohol?
Alcohol is a chemical substance that has a hydroxyl group.
We drink ethanol
What are some characteristics of yeast?
Fast generation time
Dried for long-term storage, rehydrated for use
Genome is fully sequenced
Modal organism
Why do we have multiple yeast strains available for use?
Optimized for an application like making wine vs making beer
What percent of ethanol is toxic to yeast?
15%
Distillation concentrates alcohol to which percentage?
40+%
What is proof?
Alcohol per volume
What other molecules are produced in fermentation?
Phenols
What processes are involved in fermentation?
Glycolysis
Alcohol dehydrogenase
How do we calculate ABV?
Subtract final [sugar] from original [sugar]
Multiply by 131.25
How do we calculate proof?
ABVx2
What makes up the chemical profile of alcohol?
Complex plant chemistry, yeast metabolism [+ conditioning]
What 4 categories is alcohol use split into?
Abstinent
Moderate
Bingeing
Heavy
What is binge drinking?
5 or 4 drinks on one occasion in the last 30 days for men or women
How much ethanol is in 5oz/150 mL of wine?
ABV = 12%
0.6 oz EtOH
How much ethanol is in 12 oz/355 mL of beer?
ABV = 5%
0.6 oz EtOH
How much ethanol is in 1.5 oz/44 mL of spirits?
ABV = 40%
0.6 oz EtOH
How many grams of ethanol are in 1 oz?
23.3 g
How many grams of ethanol are in a standardized drink?
13.98g
(23.3 g EtOH/oz x 0.6 oz)
Where is ethanol absorbed?
In the small intestine
How does food affect the absorption of alcohol?
Increases retention time in the stomach
Slows down absorption
Does the low pH of the stomach alter alcohol?
No
Where does alcohol distribute?
In aqueous tissues
What determines BAC?
The volume of alcohol available for distribution (g ethanol / 100 mL blood
How does a higher proportion of body fat affect BAC?
Higher BAC after one drink
What is the estimate BAC in men and women after 1 drink?
men = 0.023
female = 0.026
How is BAC affected in larger and leaner people
Larger people have lower BAC because they have greater body volume
Leaner people have lower BAC because they have a greater water volume within body volume
Why can alcohol pass into the brain easily?
Because of the small size of the molecules
What kind of phase drug is alcohol?
Biphasic
What causes the biphasic effects of alcohol?
Metabolism
What are the psychological effects of alcohol?
Inhibited decision-making
Unstable mood
Heightened emotions
Decreased anxiety
Increased aggression and addiction
What are the cognitive effects of alcohol?
Reduced time to fall asleep, less deep and REM sleep
Impaired memory
Impaired balance and coordination
Vision impeded, inhibited senses
Reduced pain perception
What are the salivary effects of alcohol?
Increased salivation and appetite
What are the cardiovascular effects of alcohol?
Dilated blood vessels of the skin
Reduced blood clotting
Increased HDL levels
What are the GI effects of alcohol?
Increased gastric HCl secretion
Increased insulin sensitivity in non-diabetics
What are the renal effects of alcohol?
Inhibited anti-diuretic hormone and increased urination
What are the reproductive effects of alcohol?
Inconsistent effects on reproductive system
What are the physiological effects of alcohol?
Vasodilation by autonomic brainstem nuclei
Increased gastric/salivary secretions
Loss of stomach mucosal lining causing ulcers
How does alcohol affect neuron activity?
It slows it
What neurotransmitters are affected by alcohol?
GABA
Glutamate
Dopamine and endogenous opioids
Other NTs
What are the anxiolytic effects of alcohol due to?
The amygdala
Where is alcohol metabolized?
In the liver (90%)
-ADH-ALDH (most)
-CYP2E1 catalase
2% excreted untouched in breath,skin, and urine
3% metabolized in the stomach
5% other
How does ADH-ALDH work?
Ethanol is broken down into acetaldehyde by ADH and into acetyl CoA by ALDH and then into CO2 and H2O
What type of kinetics describes alcohol metabolism?
Zero order
What is the difference between 0 order and 1st order kinetics?
0 = linear elimination curve
1st = exponential elimination curve
What is the elimination rate of alcohol?
0.015 BAC per hour in average person
What BAC is lethal?
0.4-0.5%
What does the BrAC measure (roadside test)?
Amount of alcohol exhaled is 1/2100th the concentration in the blood
How does alcohol cause the spins?
EtOH permeates the endolymph and the cupula
BAC starts to decline so EtOH diffuses out of the cupula before the endolymph
The cupula is now more dense than the endolymph and does not stabilize when lying down which activated sensory fibres that interprets this as motion
What underlies memory loss following alcohol use?
Depressed hippocampal activity
What drives the septohippocampal pathway?
ACh activity
What can over-suppressed activity by high dose ethanol cause?
Transient anterograde amnesia
What neurons are particularly susceptible to ethanol damage?
Hippocampal dentate gyrus neurons
What can chronic alcoholism coincide with?
Nutritional deficiencies like thiamine
What is alcohol-related brain damage driven by?
Pro-inflammatory signaling that induces cellular damage and death
How does antifreeze poison us?
It is broken down into glycolic acid and oxalic acid which causes stupor/coma as well as hyperventilation/arrhythmia/lung edema
How does methanol poison us?
It is broken down into formaldehyde and formic acid which causes blindness by damaging the optic nerve mitochondria and eventually causes respiratory failure
How does isopropanol (hand sanitizer) poison us?
metabolized to acetone which causes vomiting and coma at high concentrations
How can methanol poisoning be treated with ethanol?
Out-competes methanol for metabolic enzymes which reduces production of formaldehyde so that methanol can be excreted unchanged via kidneys
How can methanol poisoning be treated with fomepizole?
It is a competitive inhibitor of alcohol dehydrogenase, prevents build-up of toxic metabolites
What did early studies suggest about the effects of ethanol on the brain?
EtOH inhibits soluble enzyme
i.v. EtOH increases VTA DA-ergic firing frequency
10-200 mM EtOH increases spontaneous VTA firing frequency in vitro
EtOH must be applied directly in VTA, not in NAc
What is the mechanism of ethanol action?
Reduced electrical activity
When is there a strong potentiation of GABA receptors?
At lower [EtOH], especially delta subunit-containing which may be extra-synaptic
When are iGlu-NMDA receptors and voltage-gated Ca2+ channels inhibited?
At higher [EtOH]
What is the overall effect of the mechanism of EtOH action?
Neuronal inhibition, sedative-like effects
Why can alcohol consumption induce asphyxiation?
Can cause asphyxiation at lethal doses because of depressed activity in autonomic centres
What neurotransmitters balance activation and inhibition?
Glutamate and GABA
Most important for EtOH reinforcement
Where do Glu-ergic neurons input?
Input to VTA from PFC, RN
Where do GABA-ergic neurons input?
Inputs to VTA including NAc, VTA interneurons
What are the characteristics of GABAa receptors?
Cys-loop ligand-gated channel
Heterpentameric receptors
19 genes give rise to 19 subunits
What do alpha4delta-containing GABAa receptors respond to?
Low EtOH and is expressed in the striatum (reward circuit)
Causes hyperpolarizing currents
EtOH potentiates channels after activation
What are the characteristics of NMDA receptors?
Ionotropic
Heterotetrameric
Subunits arise from 1 NR1 gene, 4 NR2 genes, and 2 NR3 genes
Subunit composition directly affects function
Which NR1/2 is the least sensitive to ethanol?
NR1/2C
How does high doses of ethanol affect NMDA receptors?
Inhibited at high doses which has an addictive effect with GABA potentiation towards overall depressed electrical activity
Which individuals are predisposed to alcohol abuse?
Those with low baseline levels of endorphin because they release more when given alcohol
What input does VTA DA-ergic neurons receive from the arcuate nucleus of the hypothalamus?
Opioid-ergic
What controls the VTA DA-ergic firing to the NAc?
GABA-ergic inputs
Decreased Glu-ergic inputs + increased opioid-ergic inputs = less active GABA-ergic interneurons = phasic firing of VTA to NAc
What happens as BAC rises?
Triggers VTA to NAc DA release which causes disinhibition
What happens as BAC drops?
Potentiates GABAa receptors IPSPs
Blocks NMDA receptor EPSPs
Blocks select Ca channels
Overall depressed electrical activity
How does alcohol tolerance affect receptors?
GABAa receptor functions decrease
NMDA receptors are up-regulated
Ca channel receptors up-regulated
What happens to the brain as one becomes tolerant to alcohol?
Over-active brain, hyperexcitable which leads to emotional volatility and increased tolerance to other drugs that affect GABA receptors
What is a behavioural mechanism of alcohol tolerance?
Masking of inebriation
What is a metabolic mechanism of alcohol tolerance?
Up-regulation of live enzymes, especially in heavy drinkers
What enzyme level increases with alcohol tolerance?
CYP2E1
Overactive CYP2E1 induces more EtOH damage
What is alcohol withdrawal syndrome (hangover)?
Physical and psychological symptoms
What are the physical symptoms of a hangover?
Headache, diarrhea, fatigue, restlessness, nausea
What are the psychological symptoms of a hangover?
Haziness, slower thought/cognition, impaired reaction times, poor reasoning
When do hangover symptoms peak?
Peaks as BAC reaches 0, metabolites continue to cloud brain function
What is a congener?
A minor chemical constituent, especially one that gives a distinctive character to a wine or liquor or is responsible for some of its toxic effects
What does increased congener of a drink lead to?
Increased hangover severity
What is stage 1 of alcohol withdrawal?
Elevated heart rate/bp
Diaphoresis (sweating)
Tremors
No appetite
Insomnia
What is stage 2 of alcohol withdrawal?
Hallucinations
What is stage 3 of alcohol withdrawal?
Delusions
Delirium
Amnesia
Tremens
What is stage 4 of alcohol withdrawal?
Seizure
How do we treat AWS?
By reducing over-excitation
How do glutamate antagonists treat AWS?
Reduce hyperexcitability
How does benzodiazepines or ketamine treat AWS?
Reduces AWS severity
How does clonidine treat AWS?
Pre-synaptic alpha2 adrenergic agonist that prevents excessive neurotransmitter release
How does propranolol treat AWS?
Beta adrenergic antagonist that reduces sympathetic effects and tremor
How does disulfiram treat AWS?
Inhibits acetaldehyde dehydrogenase, build-up of acetaldehyde, aim is to prevent alcohol use but does not decrease cravings
How do naltrexone and nalmefene opioid antagonists treat AWS?
Prevent DA-ergic reward
How can we explore neural circuity?
Imaging, electrophysiology
3D reconstructions to picture synaptic connections
Electrical potentials across particular membranes to track LTP/LTD
Molecular signaling to understand how cells are regulating cellular changes that underlie electrical changes
What type of neuroadaptations underlie long-term dependence on alcohol?
Glu, GABA
Dopamine, 5HT, opioids, corticotrophin-releasing factor
Changes in reinforcement, enhanced anxiety, increased sensitivity to stress
What do structural neuroadaptations represent?
Alterations in the space available for synaptic connections and are among the major neurobiological adaptations by which experience alters the brain in the service of future behaviour
Where are Glu-ergic synapses located?
Almost entire on the head of spines
What are the two regions in the nucleus accumbens?
Core and shell
What do stubby and mushroom shapes in the NAc mean?
Stubby = immature
Mushroom = mature
What do scaffolding proteins support?
Synapses
When are changes to protein levels and synaptic connections in the NAc neurons most prominent?
During alcohol withdrawal
What are the effects of alcohol on the central amygdala?
Increased GABA release in the central amygdala and basolateral amygdala
Indicated by measuring mini inhibitory post-synaptic currents
Why do alcoholics have reduced brain volume?
Neurons die off induced by ROS/acetaldehyde production in the brain
How does alcohol abuse change brain health and appearance?
Affects glucose metabolism, protein synthesis, myelin formation = damages neurons and causes cell death
Hyperactive Glu systems cause excitotoxicity via excessive Ca influx leading to cell death
Why can alcoholism cause a thiamine deficiency?
Because the GI tract is irritated and can’t absorb it from food
What can nutritional deficiencies due to alcohol abuse cause?
Wernicke’s encephalopathy
Korsakoff’s confabulation to cover memory loss, disorientation, loss of coordination
Who is more prone to drinking more alcohol?
People with low baseline beta-endorphin levels
Why do heavy drinkers often suffer from malnutrition?
EtOH contains more energy than carbs or protein
Can be accompanied by metabolic changes in energy use, the brain metabolizes acetate and not glucose
Which reactive species does CYP2E1 produce?
Acetaldehyde and ROS
What does ROS react with under controlled conditions?
Anti-oxidant systems
What does ROS react with under elevated conditions?
Anti-oxidant system is overwhelmed
Reacts with protein, lipids, DNA
What happens if the cell cannot detoxify from ROS?
Becomes stressed
Stress leads to membrane and DNA damage, cancer, cell death
How does fatty liver disease come about in alcoholics?
Metabolic switch in the liver
Metabolism produces high levels of NADH relative to NAD+ which reduces fatty acid oxidation
Excess fat is stored in droplets and cells start to lyse and induce inflammation which can lead to hepatitis
What can fatty liver disease progress to?
Cirrhosis
What is cirrhosis?
Chronic inflammatory state and death of the liver
How does cirrhosis come about?
TGF-beta cytokine production by infiltrating immune cells triggers transcriptional changes
Cells begin producing collagen that is dumped into the extracellular space
Functional liver cells are replaced by fibrous, collagenous matrix
What ability does the liver lose after cirrhosis?
Irreversibly loses detoxifying capacity
What doe retinoic acid receptors do?
Reduces cell proliferation
Anti-cancer
Reduced expression in stressed cells
How does the immune system mis-identify targets in the liver of alcoholics?
Immune cells become activated within the liver
Starts targeting cells it deems foreign
Progression to cancer requires massive dysfunction
Reactive lipids are highly mutagenic
What percent of cancer is related to alcohol consumption?
50%
Why is the upper GI tract susceptible to cancer in alcoholics?
Microflora contribute to EtOH metabolism
Acetaldehyde can reach 10-100x higher concentrations than in the blood
Poor hygiene increase microbe count
Smoking increases acetaldehyde production
What is 4MP?
An alcohol dehydrogenase inhibitor
What are the mechanisms of oncogenesis in alcoholics?
Acetaldehyde interferes with DNA synthesis and repair
Binds and inactivates DNA repair proteins
Causes mutations and chromosomal abnormalities
What does acetaldehyde + DNA =?
N2-ethylidene-dG
What does 2 acetaldehyde + guanine =?
Propanodeoxyguanosine
What happens when complexes encounter modified bases?
DNA synthesis stops
What are the effects of alcohol spectrum disease?
Developmental stages are adversely affects at different times for different regions
Face and brain development are vulnerable in the 3rd week
Brain development is vulnerable in the 3rd trimester
Poor impulse control and planning
What are the physical features of alcohol spectrum disease?
Small head
Low nasal bridge
Epicanthal folds
Small eye openings
Flat midface
Short nose
Smooth philtrum
Thin upper lop
Underdeveloped jaw
What are the cardioprotective effects of alcohol consumption?
Low doses, 1 drink per 1-2 days
Increases HDL which prevents lipid deposition in arteries, decreases platelet aggregation
What are the cardiotoxic effects of alcohol consumption?
Cardiomyopathies at high EtOH doses
Direct modulator of Ca release
Acetaldehyde inhibits protein synthesis, the heart has high protein turnover due to muscle fibre and beating function, also damages mitochondria
