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Pmcol 305 > Alcohol > Flashcards

Alcohol Flashcards

1
Q

alcohol

A

ethanol (EtOH)
hydroxyl group (alcohol functional group)

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2
Q

yeast

A

converts sugars to alcohol through fermentation
fast generation time
dried for long-term storage; rehydrated for use
simple fungi = genomes are fully sequenced → can trace metabolic pathways
model organism → aging, DNA repair, brewing

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3
Q

fermentation

A

glucose → 2 pyruvate by glycolysis
pyruvate → 2 acetaldehyde (release of CO2)
acetaldehyde → ethanol by aldehyde dehydrogenase

additional molecules are produced
15% ethanol is toxic to yeast (above requires distillation)

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4
Q

distillation

A

concentrates alcohol to 40%+

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5
Q

proof

A

ABV x 2
max proof is ~190 chemically - alcohol absorbs moisture from the air

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6
Q

ABV

A

alcohol by volume
difference in density of sugar between original and final

= 131.25 x (OG-FG)

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7
Q

wine, beer, and scotch chemistry

A

botanical beverages = plant-based

complex plant chemistry + yeast metabolism [+ conditioning (oxidation of chemicals)] = chemical profile in finished products

anthocyanins, terpenes, tannins, polyphenols, vitamins

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8
Q

alcohol use

A
  1. abstinent
  2. moderate
  3. bingeing: 4 (women) or 5 (men) drinks on one occasion in last 30 days
  4. heavy (alcoholic)

use epidemiological trends and health related effects to set definitions → start to feel negative effects

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9
Q

ethanol in a standardized drink

A

one standardized drink = 0.6 oz
1 oz contains 23.3 g of EtOH

= ~14g of alcohol

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10
Q

absorption

A

absorbed in the small intestine
partially absorbed in stomach - food increases retention time in the stomach = slowed absorption
(low pH does not alter ethanol)

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11
Q

distribution

A

distributes through aqueous tissue
small size = easily distributed to brain → psychoactive effects
volume available for distribution determines BAC
g EtOH / 100 mL of blood

higher proportion of body fat = higher BAC after 1 drink

larger people = lower BAC because of greater body volume
leaner people = lower BAC because of greater water volume

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12
Q

estimate BAC

A

blood alcohol concentration

one drink = 14g EtOH
avg man = 53.4% water; 1L water = 1kg
0.534 x 90.7 kg = 48.4L

14g EtOH / 48.4 L water = 0.29 g/L = 0.029 g / 100 mL

blood = 80.6% water
0.029 g / 100 mL x 0.806 = 0.023 BAC

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13
Q

acute effects of EtOH

A

biphasic
1. as BAC rises (~ 1st hour) = stimulant
triggers VTA → NAc DA release (disinhibition)
- increased sociability, decreased anxiety
2. BAC falls (when stopped drinking) = depressant
potentiation of GABA A receptor IPSP, blocks NMDA receptor EPSPs, blocks select Ca2+ channels
- feel and show inebriation

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14
Q

acute effects in brain

A

inhibited decision making
unstable mood and heightened emotions
decreased anxiety
increased aggression + addiction

impaired memory, balance + coordination, vision
balance: improper cerebellum-mediated modulation of motor signals

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15
Q

acute effects in heart

A

1st phase = increased heart rate
2nd phase = decreased heart rate

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16
Q

acute effects in blood vessels

A

vasodilation
autonomic brainstem nuclei
causes warm skin but decreased core temperature

reduced blood clotting

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17
Q

other acute effects

A

increased salivation + appetite
inhibited ADH hormone = increased urination
reduced perception of pain

increased gastric secretions
overproduction of acid = loss of stomach mucosal lining

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18
Q

mechanism of action

A

depressant: slows neuronal activity
affects neurotransmitters: GABA, glutamate, dopamine + endogenous opioids, other NTs

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19
Q

aggression

A

inhibition of PFC areas that control behaviours
many environmental factors

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20
Q

GABA

A

alcohol increases GABA’s inhibitory actions
potentiates GABA receptors

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21
Q

glutamate

A

alcohol blocks glutamate receptors

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22
Q

dopamine and endogenous opioids

A

alcohol increases the release of dopamine and endorphins in addiction pathways

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23
Q

other neurotransmitters

A

alcohol affects serotonin + endogenous cannabinoids

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24
Q

anxiolytic effects

A

amygdala
decreased activity when threatened = don’t perceive threats

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25
Q

mechanism of reinforcement

A

acute ethanol inhibits glutamate and stimulates opioid neurons in hypothalamus
causes inhibition of GABA interneuron → disinhibition of dopaminergic neuron in nucleus accumbens
= phasic firing of dopamine neuron
→ addiction, reward, motivation

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26
Q

metabolism

A

causes biphasic effects

90% metabolized in liver by alcohol dehydrogenase + acetaldehyde; CYP 2E1
2% excreted by breath, urine, skin
3% metabolized in stomach
5% in brain + epithelium

genetic effects on ALDH levels, effects, vulnerability to addiction

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27
Q

zero order kinetics

A

linear elimination curve
0.015 BAC elimination per hour in avg person - same rate

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28
Q

driving under the influence

A

amount of alcohol exhaled is 1/2100 the concentration in blood → breathalyzer tests
(concentration in breath x 2100) = BAC

0.05% = provincial limit for suspension
0.08% = federal limit for criminal DUI

0.4-0.5% = lethal

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29
Q

the spins

A

common side effect of excessive drinking
BAC ~ 0.04

change in fluid density in semi-circular tubules - alcohol permeates endolymph and cupula; when BAC starts to decline, EtOH diffuses out of cupula first = cupula is more dense than endolymph, cannot stabilize when lying down
= sensory fibres are activated → brain interprets activity as motion

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30
Q

memory loss

A

depressed hippocampal activity (black out drunk)

septohippocampal pathway is driven by ACh
over suppressed activity by high doses = transient anterograde amnesia

hippocampal dentate gyrus neurons in medial temporal lobe are susceptible to ethanol damage

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31
Q

alcohol-related brain damage

A

pro-inflammatory signaling that induces cellular damage and death

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32
Q

alcohol poisoning

A

antifreeze (ethylene glycol) → metabolites =glycolic acid and oxalic acid
stupor/coma, hyperventilation/arrhythmia/lung edema

methanol → metabolites = formaldehyde and formic acid
blindness (damage to optic nerve mitochondria); respiratory failure

hand sanitizer → isopropanol metabolized to acetone
vomiting, coma

metabolites are toxic

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33
Q

treating methanol poisoning

A

administration of
1. ethanol
out competes methanol for metabolic enzymes = reduces formaldehyde production
methanol is excreted unchanged via kidneys
2. fomepizole
competitive inhibitor of alcohol dehydrogenase = prevents build up of toxic metabolites

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34
Q

lipid theory

A

early 19th century
Meyer-Overton
anaesthetics interact with lipid membranes to cause effects → affect Na+ and K+ channels
not 100% accurate

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35
Q

1980s theory

A

EtOH inhibits soluble enzyme luciferase

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36
Q

EtOH direct effect on DA somas

A

IV EtOH increases VTA DAergic firing frequency
10-200mM EtOH increases spontaneous VTA firing frequency in vitro
EtOH must be applied directly in VTA, not in NAc

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37
Q

mechanism of EtOH action

A

lower [EtOH] = strong potentiation of GABA A receptors (delta subunit → may be extra synaptic)
higher [EtOH] = inhibition of ionotropic Glu-NMDA receptors and voltage gated Ca2+ channels

= neuronal inhibition, sedative-like effects
asphyxiation at lethal doses via depressed activity in autonomic centres

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38
Q

input to VTA dopaminergic neurons

A

GABA interneurons:
- NAc - lateral shell, medial shell, and core
- ventral pallidum

glutamate neurons:
- amygdala
- medial PFC

NE neurons:
- locus coeruleus

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39
Q

neurotransmitters

A

glutamate and GABA = most common; balance activation/inhibition
→ important for EtOH reinforcement

Glutamatergic inputs to VTA from PFC, RN
GABA-ergic inputs to VTA from NAc, VTA interneurons

40
Q

GABA A receptors

A

cys-loop ligand gated channel
heteropentameric receptors
19 genes = 19 subunits

41
Q

α4δ-containing GABA A receptor

A

responds to low EtOH; expressed in striatum
= part of reward circuit (implicated in addiction)
hyperpolarizing currents, threshold mini inhibitory post-synaptic currents
EtOH potentiates channels after activation (open longer)

42
Q

NMDA receptors

A

ionotropic Glu receptor
heterotetrameric
subunits - 1 NR1 gene, 4 NR2 genes, 2 NR3 genes
subunit composition directly affects function
8 NR1 splice variants in humans

inhibited by EtOH at high doses → additive effect with GABA potentiation towards overall depressed electrical activity

43
Q

NR1/2C subunit

A

less sensitive to EtOH than NR1/2A or 2B

44
Q

behavioural tolerance

A

cerebellum → increased NR1/2C subunits = less sensitive to EtOH
masking of inebriation (balance, motor coordination)

45
Q

other input to VTA dopaminergic neurons

A

receives opioid-ergic input from arcuate nucleus of hypothalamus
individuals with low baseline levels of endorphin release more when given alcohol
= genetic predisposition to alcohol abuse (addiction is a polygenic disease)

46
Q

control of VTA DAergic firing to NAc

A

glutamatergic + opioidergic inputs to GABAergic interneurons
balance between inputs = baseline GABA activity = tonic firing of VTA → NAc

decreased glu inputs + increased opioid inputs = less active GABA interneurons = phasic firing of VTA → NAc

GABA inputs are main control

47
Q

acute → chronic effects

A

tolerance:
decreased GABA A receptor expression
up-regulation of NMDA receptors and Ca2+ channels
= over-active brain, hyperexcitable → emotional volatility

48
Q

cross tolerance

A

with other drugs that affect GABA receptors (benzos, barbiturates)

49
Q

mechanism of tolerance

A
  • GABA A receptor down-regulation (↓ expression)
    → subunit compositions and receptor localizations in membrane change
  • NMDA receptors up-regulated (hyper-excitability)
  • Ca2+ channel receptors up-regulated
    = higher excitability
50
Q

metabolic tolerance

A

up regulation of liver 2E1 enzymes
subjects showed elevated CZX metabolism (2E1 substrate)

CYP2E1 knockout prevents EtOH induced liver damage; over-active CYP2E1 induces more damage

= metabolites are the cause of damage

51
Q

alcohol withdrawal syndrome

A

hangover
physical symptoms: headache, diarrhea, fatigue, restlessness, nausea
psychological symptoms: haziness, slower though/cognition, impaired reaction times, poor reasoning

symptoms peak as BAC reaches 0 → metabolites reach max concentration = cloud brain functioni

52
Q

congener

A

minor chemical constituent that gives a distinctive character to wine or liquor (flavour and colour) - responsible for some of its toxic effects
e.g. acetone, methanol, acetaldehyde, furfural

higher congener content of a drink = increased hangover severity
brandy has 37x more than vodka

53
Q

withdrawal

A

stages 1-4
more severe than most other drugs
sympathomimetic effects

54
Q

stage 1 of withdrawal

A

elevated heart rate/bp
diaphoresis
tremors
no appetite, insomnia

55
Q

stage 2 of withdrawal

A

hallucinations
increased stimulatory response

56
Q

stage 3 of withdrawal

A

delusions, delirium, amnesia
tremors peak 3-4 days after last drink

57
Q

stage 4 of withdrawal

A

seizure

58
Q

treatment of AWS

A

prevent stages 3 and 4
reduce over excitation

  • glutamate antagonists
  • benzodiazepines or ketamine
  • clonidine
  • propranolol
  • disulfiram
  • opioid antagonists
  • SSRI, cannabinoid antagonists
59
Q

glutamate antagonists

A

e.g. acamprosate
reduce hyperexcitability

60
Q

benzos or ketamine

A

reduce AWS severity

61
Q

clonidine

A

pre-synaptic α2 adrenergic agonist
prevents excessive neurotransmitter release

62
Q

propranolol

A

β adrenergic antagonist
reduces sympathetic effects and tremor

63
Q

disulfiram

A

enzyme blocker → inhibits acetaldehyde dehydrogenase
= buildup of acetaldehyde

aversive conditioning
prevents alcohol use, does not decrease craving

64
Q

opioid antagonists

A

naltrexone, nalmefene
prevent DA reward by maintaining threshold for DA firing
reduce reinforcement by disinhibition

65
Q

neural circuitry - use of imaging + electrophysiology

A

3D reconstructions to picture synaptic connections, neuronal morphology
electrical potentials across particular membranes - track LTP, LTD
molecular signaling - how cells are regulating cellular changes that underlie electrical changes

66
Q

long term dependence - neuroadaptations

A

glutamate, GABA, DA, 5-HT, opioids, CRF

changes in reinforcement, enhanced anxiety, increased sensitivity to stress
structural neuroadaptations = alterations in the space available for synaptic connections

glutamatergic synapses located almost entirely on head of spines (direct opposition of post synaptic membrane)

67
Q

nucleus accumbens

A

two regions: core and shell
core: aversive reinforcement
shell: positive reinforcement

68
Q

Spiga et al. 2014

A

NAc medium spiny neurons spines in healthy control rat:
stubby = immature
mushroom = mature

most pronounced changes observed during withdrawal
- less spiny features overall = less activity
- long thin spines were most affected

69
Q

adhesion molecules

A
70
Q

morphological changes in NAc

A

neurons are continuously altering protein levels and synaptic connections

after 1d withdrawal: reductions in dendritic length and branching; increased mature spines in core
after 7d withdrawal: shell MSNs length and branching reduced; higher density of immature spines

spines are selectively altered (long thin but not mushroom)

71
Q

effects on amygdala

A

measure of mini inhibitory post synaptic currents = increased GABA release in central and basolateral amygdala

72
Q

gross brain changes

A

reduced brain volume
nutritional deficiency (thiamine [vit B] bc of irritated GI tract)
hyperactive Glu systems

73
Q

reduced brain volume

A

increased stress in brain → ROS/acetaldehyde production
= induces neuronal death

74
Q

nutritional deficiency

A

affects glucose metabolism, protein synthesis, myelin formation = cell death

Wernicke’s encephalopathy
Korsakoff’s confabulation → memory loss, disorientation, loss of coordination

75
Q

hyperactive glutamate systems

A

cause excitotoxicity via excessive Ca2+ influx → cell death

76
Q

increased abuse potential

A

heart rate biomarker: pharmacological indicator of stimulatory influence due to alcohol

reward circuit in the NAc elevates DA levels → brainstem nuclei raise heart rate
elevated levels of catecholamines

77
Q

genetic factors affect risk of addiction

A

low baseline beta-endorphin levels = prone to drinking more alcohol

78
Q

adolescent brains + EtOH

A

developing brain connections until 25 years = susceptible
PFC deficiencies prevent full development of consequential thinking; normally regulates reward-seeking
affects long-term hippocampal synaptic plasticity → learning + memory

79
Q

malnutrition

A

EtOH contains lots of carbs → complex in beer
easy to put on weight

+ metabolic changes in energy usage → brain metabolizes acetate, not glucose

80
Q

CYP2E1 produces ROS

A

acetaldehyde + ROS

ROS react with anti oxidant systems → at elevated levels, overwhelm the systems
can react with cellular components → stress cell if it cannot detoxify
→ membrane + DNA damage, cancer, cell death

81
Q

metabolic switch

A

metabolism produces high NADH:NAD+ → reduces fatty acid oxidation (decrease use of fat as energy source → stored)

cells start to lyse and induce inflammation → hepatitis
reversible at early stages

82
Q

fatty liver disease → cirrhosis

A

TGF-beta cytokine production by infiltrating immune cells
triggers transcriptional changes in hepatocytes

cells produce collagen → dumped into extracellular space
→ fibrosis

83
Q

fibrosis

A

functional liver cells are replaced by fibrous, collagenous matrix (clumps of non-functional tissue)
liver irreversibly loses detoxifying capacity

84
Q

cirrhosis

A

chronic inflammatory state + cell death
caused by pro-inflammatory cascade: cell death and reactive species-induced changes to macromolecules facilitate immune infiltration

mis-identification of targets:
activation of immune cells in the liver → target host antigens

85
Q

progression to cancer

A

requires massive dysfunction - local inflammatory environment
avoids immune recognition and cell death

reactive lipids are highly mutagenic

86
Q

retinoic acid receptor

A

therapeutic target
reduces cell proliferation = anti cancer
reduced expression in stressed cells

87
Q

increased cancer risk

A

upper GI tract, colorectal, liver, breat

50% of cancers linked to alcohol consumption
upper GI tract susceptible because microflora contribute to EtOH metabolism

[acetaldehyde] can reach 10-100x higher than in blood
increased production by smoking

88
Q

mechanisms of oncogenesis

A

4MP: alcohol dehydrogenase inhibitor
reduces N2-ethylidene-dG count

acetaldehyde + DNA = N2-ethylidene dG
→ free floating ROS - links to endogenous molecules

89
Q

acetaldehyde

A

metabolite
interferes with DNA synthesis and repair → binds and inactivates DNA repair proteins; causes mutations and chromosomal abnormalities

90
Q

FASD

A

fetal alcohol spectrum disorder
developmental stages in uterus are adversely affected at different times
- face + brain development: vulnerable in 3rd week
- brain development: vulnerable in 3rd trimester
→ poor impulse control, planning

91
Q

cannabinoid receptor (29)*****

A
92
Q

safe level of alcohol consumption

A

cardioprotective effects vs cardiotoxic effects

93
Q

cardioprotective effects

A

low doses, 1 drink per 1-2 days
beneficial antioxidants in wine → increases HDL = prevention of lipid deposition in arteries, decreased platelet aggreggation
= decreased CV disease

94
Q

cardiotoxic effects

A

cardiomyopathies at high doses
EtOH = direct modulator of Ca2+ release → inhibits SR Ca release = negative ionotropic effect
acetaldehyde inhibits protein synthesis; damages mitochondria

95
Q
A

Pmcol 305 (18 decks)

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