Alcohol II

Question 1

what was an old reason as to how alcohol had an effect on the brain?

Answer 1

it was originally believed that alcohol exerted its effects in the brain by non specifically disrupting lipid bilyers

alcohol can increase the fuidity of lipid membranes as can almost any anesthetic

thought that this increase in fluidity would unsettle sodium and potassium channels involved in conducting nerves

this theory is not used anymore because its shown that alcohol binds to receptors of neurotransmitters to cause its effect rather than it being due to unsetteling of lipid membrane

Question 2

What are the basic properties of a gaba-a receptor? and what is it?

Answer 2

gaba-a receptors are ligand gated (so a ligand must bind for it to do its action) ion channel (it releases ions when activated) –> a receptor whose integral ion channel is opened or closed by a binding of a neurotransmitter

there are 5 subunits of GABAa receptors

the most abundant ones are 6 types of alphas, 4 types of betas, 3 types of gammas and one type of delta which can be mixed and matched to make different gaba receptors that do different things

Question 3

where does GABA bind at the GABA-a receptors? and what happens when it binds?

Answer 3

GABA binds at the interface between alpha and beta subunits

a chloride channel sits central in the subunits and opens when activated by GABA, chloride ions enter postsynaptic cells

the negative charge on the chloride ion hyperpolarizes the membrane and inhibits depolarization of the post synaptic membrane

Question 4

how does alcohol work in terms of GABA receptors?

Answer 4

alcohol potentiates the effects of GABA but only in those receptors containing the delta subunits

alcohol present makes the post synaptic cell even more depolarized than normal GABA

Question 5

what are NMDA receptors? how are they activated and by which neurotransmitters?

Answer 5

NMDA receptors are a type of glutamate receptors that are activated by NMDA

• the receptor has 4 subunits -> two NR1 (essential) and two of any: NR2 (NR2A, B, C, or D)
• glutamate does not bind at subunit interfaces
• central ion channel that is opened upon activation allows for positively charged ions to enter post-synaptic cell (sodium and calcium)

Question 6

what effect does ethanol have on NMDA receptors?

Answer 6

ethanol inhibits receptor activity at high concentrations

and does not seem to bind to the same site as NMDA.. . and binds in the transmembrane domains instead

Question 7

what happens when NMDA receptors get over-activated?

Answer 7

in conditions where receptors are over-activated, you get excitotoxicity due to excess calcium entering the neurons

Question 8

What is ethanols main mechanisms of action on GABA and NMDA receptors at low doses?

Answer 8

ethanol strongly potentiates effects of GABA at low doses at the specific GABA-a receptors containing delta subunits.

Question 9

What is ethanols main mechanisms of action on GABA and NMDA receptors at higher doses?

Answer 9

at higher doses, ethanol inhibits the effects of glutamate on glutamate receptors while still affecting GABA-a receptors

Question 10

What are the net inhibitory effects of ethanol?

Answer 10

besides glutamate and GABA effects, it also inhibts calcium entry through voltage gated calcium channels which reduces NT release

the net effect is neuronal inhibition… dowsiness, anesthetic like properties

even though ethanol is inhibitory, it can increase the activity of some circuits because it inhibits the inhibitory control over them… removes the breaks off of some circuits in the brain

Question 11

between which subunits does alcohol bind in a GABA receptor?

Answer 11

it binds between alpha and beta subunits

Question 12

What happened when ethanol was administered right into the nucleus accumbens?

Answer 12

there was little increase in dopamine that tells us that ethanol is not the direct cause of dopamine release in the reward pathway (mesolimbic circuit)

Question 13

what happened when ethanol was administered into the ventral tegmental area (VTA)?

Answer 13

there was increase in dopamine realease from VTA neurons that synapsed with the nucleus accumbens

Question 14

what controls GABA release in the VTA? how come GABA doesnt inhibit the VTA from releasing dopamine? what is the role of mu-opiod receptors?

Answer 14

theres evidence for mu-opiod receptors on GABA releasing neurons
- ethanol increases the release of beta-endorphins which is a naturally occurring mu opiod agonist from projections that come from hypothalamus

• if you add ethanol with a mu-opiod antagonist, you get no effect on firing rate of doapmine neurons
• the mu-opiod receptor activation hyperpolarizes the membrane of GABA-releasing neurons so less GABA is released and glutamate takes over

when ethanol levels are high, mu opiod activates and causes hyperpolarization of the gaba receptors

Question 15

what is the normal presynaptic control of GABA release tonically in the VTA?

Answer 15

theres gaba and glutamate receptors on the VTA, and tonic firing occurs because of glutamate exciting the vta and causing AP, and GABA inhibiting it and causing no AP. There is a balance between glutamate and GABA receptors on dopaminergic cells in VTA

Question 16

What is the presynaptic control of GABA release in the presence of ethanol?

Answer 16

when ethanol is present, beta-endorphin levels increase and activate presynaptic mu opiod receptors which hyperpolarize the membrane and decrease GABA release

glutamate then ends up having a larger effect because less GABA is released and the system becomes unbalanced

Question 17

What are 3 physiological effects of ethanol?

Answer 17

1. vasodialation through central vasomotor control mechanism in brainstem… you feel warm because the heat is radiating from core to your outer surface of body.. you can get hypothermia from drinking too much ethanol in the cold because ur internal organs and everything start to freeze
2. increased salivary and gastric secretion .. promoting hunger in some people
3. damage to gastric mucosa… bleeding via constant irritation of the stomach lining.. you damage the cells in the GI tract

Question 18

What is the effect of ethanol on GABA-a receptors, NMDA receptors, and calcium channels? how does this produce tolerance?

Answer 18

alcohol potentiates the action of GABA at GABA-a receptors, so GABAa receptors decrease when alcohol is frequently consumed

because alcohol inihbits actions of glutamate at NMDA receptors, the brain produces NMDA receptors

because alcohol inhibits calcium channels, the brain produces more calcium channels

Question 19

how does behavioural tolerance to ethanol form?

Answer 19

behavioural tolerance is common and people often modify their behaviours to mask the effects of ethanol … so like high functioning alcoholics

Question 20

how is there a metabolic tolerance to alcohol? What are some problems that arise from this?

Answer 20

CYP2E1 is upregulated significantly in chronic users, and can end up metabolizing up to 50 or 60% of total ethanol (as composed to 20% in non chronic users)

a problem: CYP2E1 METABOLIZES ACETAMINOPHEN, INDUSTRIAL SOLVENTS AND SOME ANESTHETICS INTO TOXIC METABOLITES… SO NORMAL THERAPEUTIC DOSE OF TYLENOL CAN BECOME EXTREMELY TOXIC

so CYP2E1 makes very dangerous metabolites

Question 21

What were the results of the experiement where CYP2E1 coded gene was knocked out in mice? and when mice were gentically engineered to show more CYP2E1 levels?

Answer 21

when CYP2E1 was knocked out in mice, there was less ethanol induced liver damage

when CYP2E1 was in high levels it showed more ethanol induced liver damage

other experiments also showed that as CYP2E1 increased, so did the amount of reactive oxygen species which are dangerous (free radicals)

Question 22

How does CYP2E1 produce reactive oxygen and nitrogen species?

Answer 22

up-regulated CYP2E1 is one of the major producers of reactive oxygen species (ROS) in the liver and other organs

CYP2E1 uses molecular oxygen in the normal process of metabolizing ethanol into acetaldehyde

CYP2E1 can produce ROS if the reaction does not go to completion and the oxygen does not get incorperated into the ethanol molecule.. so the oxygen escapes if theres too much ethanol around

A small amount of ethanol metabolized by normal levels of CYP2E1 at 20% produces SOME reactive chemicals but those chemicals are quickly detoxified by chemicals in the body.

After chronic use of ethanol, higher CYP2E1 activity results in high levels of ROS that the body cant detoxify
- this leads to membrane damage and cell death

DNA damage can cause cancer as well

Question 23

what areas (3) does ROS interact with and damage?

Answer 23

1. DNA
2. Lipids
3. Proteins

Question 24

What is the best guess for why hangovers occur?

Answer 24

most likely that it is due to the immune system being triggered

immune cell signalling molecules called cytokines which are abdunant in the hippocampus cause a link to memory loss

Question 25

What are congeners?

Answer 25

congeners are toxic byproducts of alcohol production which cause inflammation to humans

Brandy and red wine have the most amount of congeners which could be why they cause really bad hangovers

beer and vodka have the least amounts of congeners

Question 26

How does a beer belly occur?

Answer 26

ethanol like beers is an abundant supply of calories but no nutritional value

ethanol becomes approx 50% of the total caloric intake of an alcoholic which means they miss out on alot of vitamines etc…

alcohol has more energy per gram than protein or carbs

Question 27

How does a fatty liver occur?

Answer 27

ethanol metabolism by ADH produces NADH

this is a signal to synthesize fat and stop fatty acid oxidation

the fat is stored as droplets in cells and can get to the point where cells can lyse

a fatty liver can be reversible as long as it hasnt progressed to the point where cell death is occuring

alot of NADH levels mean that theres ALOT of energy that the body needs to store… more alcohol = more energy

Question 28

what is cirrhosis and how does it occur?

Answer 28

cirrohisis occurs when people drink more while having fatty liver

cirrhosis is a chronic inflammatory state and cell death of the liver

ethanol induces the production of transforming growth factors (TGF-alpha) in hepatocytes (liver cells)
this leads to stimulation of collagen synthesis

eventually, a functional liver cell is replaced by non functioning connective tissue (collagen) and becomes tough and scar-like looking

as the functionality of the liver changes, it loses ability to detoxify blood

Question 29

How does the immune system react to ethanol to cause liver inflammation? What is it caused by?

Answer 29

• ROS and acetaldehyde modify lipids and proteins and the body sees the modified versions as forgein and develops anti bodies to them… which explains how the immune system is involved in the liver and causes it to be chronically inflammed

ethanol exposure causes liver cells to release chemical signals called cytokines and chemokines that attract immune cells

immune cells infiltrate the liver and release ROS and RON (reactive nitrogen) as well as enzymes that destroy liver cells….

so basically cytokines think that theres something forgein there but when it gets there theres nothing but it still releases the inflammatory response which kills nad damages the healthy liver cells and causes more inflmmation to the area via signalling

Question 30

What is the idea of bed spins?

Answer 30

a reason for the cause of positional alochol vertigo/nystagmus(involuntary eye movement)

approx 30 mins after consuming ethanol, the cupula in the semicircular canals of the inner ear becomes lighter than surrounding endolymph but after 3 to 5 hours of drinking it becomes stabilized (called the silent phase where density of cupula and endolymph equalize)

once you start to break down ethanol and stop drinking about 5-10 hours after consumption, the ethanol leaves the cupula first making it heavier compared to the endolymph, which gives you the illusion that you are spinning, especially when you’re sleeping or passed out and your other senses are shut off