alcohol 2 Flashcards
1
Q
what kind of receptors are GABA A
A
ligand gated ion channel
2
Q
what happens when GABA A are activated
A
ion channel opens and Cl- flows in
3
Q
how many subunits in GABA receptor
A
5
4
Q
what happens to the cell once Cl- enters cell via GABA receptor
A
hyperpolarizes the membrane/ inhibits depolarization
5
Q
what are the most common subunits in GABA receptors
and how many kinds of each
A
alpha (6 kinds)
beta (4)
gamma (3)
delta
6
Q
what are the constant and variable types of receptors in GABA
A
2 alpha 2 beta always
then gamma or delta
7
Q
where does GABA bind
A
at interface between alpha and beta subuntits
8
Q
what does alcohol do to GABA
A
potentiates the effects of GABA
9
Q
which receptor is most likely included in GABA when it is most effected by alcohol
A
delta
10
Q
which subunits respond to low ethanol levels that most humans would experience
A
delta
11
Q
what region of the GABA receptor does ethanol interact with
A
in the receptor that interfaces with lipid bilayer
12
Q
what does ethanol do to Cl- influx into cell (via GABA)
A
it increases Cl- influx into the cell
13
Q
what happens when a single GABA molecule goes to the receptor
A
not much, usually need 2
14
Q
are there more Cl- usually on inside or outside of cell
A
more on outside
15
Q
what synthetic molecule activated NMDA receptors
A
N-methyl D aspartate (NMDA)
16
Q
what are the subunits for NMDA receptors (how many of each)
A
4 per receptor
- two NR1 (essential)
- two of any NR2 (A B C or D)
17
Q
where does glutamate bind
A
not at the subunit interface
but more on the sides kinda
18
Q
does glutamate bind at the subunit interface
A
no
more on the sides
19
Q
what happens when NMDA receptors are activated
A
Na+ and Ca2+ ion channel opens and they enter the cell
-depolarization
20
Q
does depolarization or hyperpolarization happen with NMDA activation
A
depolarization
21
Q
does depolarization or hyperpolarization happen with GABA Areceptor activation
A
hyperpolarization
22
Q
what does ethanol do to NMDA
A
inhibits them at high concentrations
23
Q
what concentrations of ethanol are required to inhibit the NMDA receptor
A
high
24
Q
are higher concentrations of ethanol required to affect the GABA or the NMDA pump
A
higher concentrations are required to inhibit the NMDA receptor than activate the GABA receptor
25
where does ethanol bind on the NMDA receptor
NOT the same as where NMDA binds
| probably in transmembrane domains that interface with the lipid bilayer
26
what can be dangerous with NMDA receptors
excess activation, leading to excitotoxicity due to excess calcium
27
what is excitotoxicity
when NMDA receptors are over stimulated so excess ca enters and becomes toxic
28
what could cause the neuronal loss seen in alcoholics
too much ca entering the cell, excitotoxicity (excess NMDA activation)
29
does GABA R or NMDA R have more subunits
GABA - 5
| NMDA - 4
30
where are the GABA A R with delta
not actually in synaptic left, more in like axons and dendrites and even cell body
31
what does ethanol do to Ca channels
| what does this cause
inhibits Ca entry through voltage-gated Ca channels
| -reduces NT release
32
what is the net effect of alcohol on neurons
neuronal inhibition (drowsy, anesthetic), shut down basic autonomic functions, death
33
does the alcohol dose that affects GABA affect dopamine release
yes DA is released at lower levels than GABA is activated
34
what is the controversy over delta subunits
they maybe delta subnuits dont play a role in sensitivity to low concentrations of ethanol, they dont know
35
what happens when you administer ethanol directly on the NAc
little if any dopamine release
| still just tonic firing
36
what happens when you administer ethanol directly on the VTA
- phasic firing, neurons depolarize with increased frequency
| - increased DA release from VTA that synapse onto NAc
37
why do VTA DA neurons fire more often with ethanol when the rest of brain has decreased excitability (with ethanol present)
there are mu-opioid receptors on GABA releasing neurons which are activated by beta-endorphin which inhibit GABA release
38
what causes the release of beta-endorphin
ethanol
39
where does beta-endorphin bind (specific)
mu opioid agonist from projects that come from the hypothalamus
40
what happens when mu-opioid receptors are activated
inhibit voltage-gated calcium channel function, increase K+ channel function - causes hyperpolarization and decreased NT release
41
what is the effect of mu opioid receptor activation on GABA neurons
less GABA released
42
which part of the brain has mu receptors on GABA releasing neurons
VTA
43
what is the net effect when GABA is inhibited by mu opioid
glutamate still works, therefore excites DA releasing neurons in VTA
44
what happens do vessels with alcohol and how
vasodilation through central vasomotor control mechanism in brainstem
45
what happens to body heat with alcohol
feeling warm but core temp may decrease
46
what happens to digestive system with alcohol
may increase salivary and gastric secretion, hunger
| but it eventually damages gastric mucosa - bleeding + irritation
47
explain the pharmacodynamic tolerance for ethanol (3)
```
downregulate GABA (an maybe changes subunit types to make less sensitive)
upregulate NMDA
upregular Ca channels
```
48
what is behavioural tolerance
modify behaviours to mask effects of ethanol
49
what is metabolic tolerance mainly with alcohol
upregulation of CYP2E1
50
how much % does CYP2E1 metabolize in alcoholics
50-65%
51
what else does CYP2E1 metabolize besides ethanol
| and what does it turn them into
acetaminophen (tylenol), industrial solvents and some anesthetics into toxic metabolites
52
are CYP2E1 levels variable in humans
yes, can have 8X variability
53
what happens to CYP2E1 levels when volunteers were given 40g of ethanol a day for 5 week
some people had a large increase in CYP2E1 levels and some had a minimal increase
54
what happens to ROS levels with CYP2E1 increase
they increase
55
what happens with CYP2E1 knockouts in mice (what happens to liver)
they show less ethanol-induced liver damage
56
what happens in mice with high CYP2E1 (what happens to liver)
they show more ethanol-induced liver damage
57
what does upregulated CYP2E1 do to ROS
increases ROS in liver and other organs
58
what is one of the major producers of ROS
up regulated CYP2E1
59
what can ROS damage
DNA
lipids
proteins
60
how does CYP2E1 metabolize ethanol into acetaldehyde (what does it use)
uses molecular oxygen to do it
61
how can CYP2E1 produce ROS
as a byproduct if the reaction does not go to completion and oxygen does not get incorporated into the ethanol molecule
62
what does a high level of ROS do to membrane
causes cell membrane damage which releases reactive lipid species from membrane -DNA damage
63
how can chronic ethanol use cause cancer
high ethanol=high CYP2E1=high ROS =cell membrane damage=reactive lipid species from membrane=DNA damage=cancer
64
how does body handle small amounts of ethanol that leads to ROS
small amounts can be more easily handled, we have many mechanisms to detox the ROS
65
what are physical symptoms of hangovers
```
headache
diarrhea
fatigue
tremulousness
nausea
```
66
what are psychological symptoms of hangovers
decreased cognition, impaired visual spatial skills
67
what BAC has symptoms peak
0%
68
can cognition be impaired even though undetectable levels of ethanol in plasma
yes! studies show impaired functioning of pilots, drivers, skiers
69
is dehydration the main cause of hangovers
no, rehydration only has a small effect on decreasing symptoms
70
what do hangovers increase the production of
cytokines
71
what does thromboxane B2 pathway do
produces cytokines
72
what is likely the main cause of hangovers
increased cytokine production
73
what is good evidence that hangovers could be caused by increased cytokine production
symptoms resemble viral infection & direct cytokine injection causes many hangover symptoms
74
what is tolfenamic acid
a prostaglandin synthesis inhibitor
75
what does tolfenamic acid do to hangovers and how
reduce symptoms by preventing cytokine production (prostaglandin synthesis inhibitor)
76
what organelle is affected in hangovers and what happens and where
mitochondrial dysfunction in cerebellum
77
what happens in cerebellum
integration of metabolic and sensory pathways
78
what can mitochondrial dysfunction due to ethanol cause thats bad?
neuronal dysfunction or death
79
what pathway does thromboxane b2 come from
prostaglandin synthesis
80
what are congeners
toxic byproducts of alcohol production and storage
| colors, flavours too
81
what are examples of congeners (6)
acetone, methanol, acetaldehyde, tannins, furfural, fusel oil
colors, flavours too
82
what color drinks tend to contain more congeners
dark
83
how much more congeners are in bourbon than vodka
37X
84
what does congeners do to hangovers
increased severity of hangover symptoms
85
how many calories/gram in alcohol
7
86
how many calories/gram in carbs
4
87
how many calories/gram in protein
4
88
how many calories/gram in fat
9
89
what % of calories of average male canadian drinker comes from alcohol
13%
90
what % of calories of average female canadian drinker comes from alcohol
8%
91
what does the brain use as fuel in brains of heavy drinkers
switches from glucose to acetate during intoxication
92
do alcoholics metabolize more or less glucose than non drinkers when intoxication
drinkers metabolize less ethanol
93
what happens to NAD+ in ethanol metabolism and how
gets converted into NADH by alcohol dehydrogenase
94
what does a high NADH:NAD+ ratio do to body fat metabolism
signals to synthesize fatty acids and stop fatty acid oxidation
95
when does your body usually signal for fatty acid oxidation
when your body needs energy
96
when does your body usually signal fatty acid synthesis
when you have lots of excess energy
97
why does alcohol make a high NADH:NAD+ ratio
because there is an abundant energy source, so you store energy
98
where does the synthesized fat go
stored as droplets in hepatocytes in liver
99
what can happen when there is lots of fat in liver cells
they can cause cell lysis and inflammation
100
is fatty liver reversible
yes if there isnt significant cell death
101
what is fatty liver
high energy input from ethanol causes fat droplets to accumulate in adipocytes
102
when does cirrhosis occur/for who does it occur
follows fatty liver if drinking continues
103
is cirrhosis reversible
no
104
what causes cirrhosis (general)
chronic inflammation and cell death
105
what is TGF-beta
a transforming growth factor, a cytokine
106
where does TGF-beta come from
liver cells
107
what does TGF-beta do
binds to cell surface receptor of liver cells and stimulates intracellular pathways that affect gene transcription
-stimulates collagen synthesis
108
what happens once cirrhosis progresses
functional liver cells are replaced by functioning connective tissue, mostly collagen
-cant detox blood as good
109
what causes collagen synthesis in cirrhosis
TGF-beta binds to receptor and stimulates gene transcription
110
what 2 compounds/molecules can modify lipids and proteins
ROS and acetaldehyde
111
what does ROS and acetaldehyde do to lipids and proteins
modifies them so the body sees them as "foreign" - develops antibodies
112
what causes the involvement of the immune system in alcoholic liver disease and inflammation
ROS and acetaldehyde modifies lipids and proteins them so the body sees them as "foreign" - develops antibodies
113
how can ethanol cause inflammation
liver cells release cytokines that attract immune cells (binding to specific cytokine receptors on these cells)
also the antibodies due to ROS affecting lipids and proteins
114
what do the activated immune cells do
infiltrate the liver, release ROS and RNS (reactive nitrogen species) + enzymes that destroy liver cells (usually kill pathogens)
