-
The first substance of abuse
that I'll be talking about is alcohol,
-
so two things -- or one thing
that you should remember --
-
Well, one of many things you
should remember, the first thing
-
you should remember is
sedative and CNS depressant.
-
What that means is, alcohol
will cause drowsiness,
-
it'll make you go to sleep
at a high dose,
-
and it's an over-suppression,
or depressant, of your nervous system.
-
So, it basically has an over-inhibitory --
inhibitory influence
-
on your nervous system.
-
So, let's dive into it.
-
So, first, I have to tell you that
there are different forms of alcohol.
-
So, the one that we drink
is active alcohol, also known as ethanol.
-
But there's also -- I mean, there are
many different types, but let's just
-
talk about these three.
-
The other one is methyl alcohol,
we also call that methanol.
-
This is extremely toxic, so
you don't want to drink this ever,
-
and that can actually --
That can cause death.
-
So, one of the metabolites of this
is formaldehyde, and we never drink
-
formaldehyde.
-
So, there was actually an article
and recall -- Not necessarily a recall,
-
but warning about some of
the hand sanitizers that are
-
being distributed right now, and because
of the shortage, there might be some
-
hand sanitizers that are not made
in the best way, and they are finding
-
some methanol in these hand sanitizers,
so definitely need to be careful.
-
And then the other type of alcohol
is isopropyl alcohol;
-
we typically know them
as rubbing alcohol. Okay.
-
Couple of things to talk about.
Alcohol, other than caffeine,
-
alcohol is the most commonly used
psychoactive drugs, and also,
-
in America, and it is most abused drug
as well.
-
We may not talk about this, or we may not
hear about this as much as
-
some other drugs, because these are
legally available, but it is most used
-
and most abused, other than caffeine.
-
Now, ethanol is produced the fermentation
of sugars by yeasts, so if you --
-
You know, you can make wine out of grapes,
sake out of rice, beer from grains.
-
The first time that we start seeing
serious alcohol abuse issues is
-
around the time when gin was produced,
so that's when people learned to make,
-
to distill the alcohol, so basically they
can make much higher concentration
-
of alcoholic beverages, and that's when we
started seeing the rise of alcohol abuse.
-
Even though alcohol has high calorie,
it doesn't provide any nutrients,
-
so it's not really good form of, you know,
supplementing your diet.
-
Okay, so, let's briefly talk about
the behavioral effects of alcohol,
-
and the behavioral output is actually
quite dose-dependent.
-
So, first of all, as low as .04%
of alcohol concentration in your blood
-
will start influencing your
behavior output.
-
So, you can sort of see in this chart
that it goes all the way up
-
to lethal dose, so that's LD 50,
right, lethal dose for 50% of the people.
-
It generally starts out with relieving
your anxiety, which then goes into
-
disinhibition, so you guys can easily
think of examples of your friends
-
or yourself, where you become
the life of the party, right?
-
Because with a little bit of alcohol,
you become a lot more talkative,
-
so that's the state that you are in,
but then if you continue to consume
-
alcohol, you get to the point where you
become sleepy and then you fall asleep,
-
but if you go past that point, then you
are starting to get to the point of where
-
you fall into a coma, and then with
really high dose, you can actually die
-
from alcohol in the system.
-
Okay, so in the next slide, let's talk
about how alcohol gets into our system.
-
It is a passive diffusion, that means
it just moves from wherever the alcohol
-
is highly concentrated to wherever
the alcohol is not highly concentrated.
-
So, typically, we drink alcohol, so
that means it goes into our GI tract,
-
that's where it's highly concentrated
-
So, it will diffuse into or seep into
your blood system.
-
So, that's how the alcohol moves.
-
So, if you have a lot of alcohol in
your GI tract, then it will get into
-
your blood system, or more of it
will go into your blood system
-
than if you don't have as much, and
that's what the Graph A is showing you.
-
So, there are different volumes
of ethanol that has gone into the system,
-
and you see that -- orally -- and then
you see this different blood-ethanol
-
concentration based on the volume
that was ingested, and because
-
it gets -- we drink alcohol and it goes
through this diffusion process,
-
if you have something in your stomach,
it will sort of interfere with
-
this diffusion process, and it will
dilute out the concentration,
-
so -- And you guys, you know,
those of you who drink alcohol
-
probably know this, that if you
drink something on an empty stomach,
-
it affects your functioning much greater
than if you had a meal, so that's what
-
the graph below is showing you.
-
Okay, so, in the next slide, let's talk
about alcohol metabolism.
-
Ninety-five percent of your alcohol
is going to metabolize by the liver,
-
and that's partly why if you abuse
alcohol, you eventually end up with
-
serious liver issues, because, you know,
it's doing a lot of work to break down
-
and get rid of this alcohol.
-
So, and then, about 5% gets taken out
by your lungs, and that's how
-
the breathalyzer works, because you can
detect presence of alcohol through
-
just your breathing.
-
Now, I usually don't spend a lot of time
talking about the metabolic process
-
of different substances, but
I'm going to have to talk about
-
alcohol metabolic process.
-
So, alcohol goes through two steps
to finally get to the point
-
of inactive form, which is a form that
no longer affects our body, and that
-
will be acidic acid, but there is
an intermediate step.
-
Alcohol gets converted to acetaldehyde,
and then acetaldehyde will get converted
-
to acidic acid, and
why do I care about this?
-
Because acetaldehyde is actually
quite toxic for our body, so it is
-
beneficial for us to basically
get rid of or break down acetaldehyde
-
right away when alcohol
gets converted to it,
-
but there is a genetic difference
in human population where the enzyme
-
that breaks down acetaldehyde,
so acetaldehyde dehydrogenase,
-
doesn't always work properly, and
higher percentage of East Asians have
-
this variation in this genetic makeup,
and that's why you might see --
-
Some of your friends might turn
bright red as they drink something,
-
and they might have much severe reaction
or severe hangover the next day
-
if they drink it, and that's because
all this flushing, nausea, headache,
-
and what we typically say "the hangover,"
or reaction to alcohol, is really due to
-
a reaction to the presence
of acetaldehyde, so if you don't
-
break down this readily, then you are
basically having a buildup of acetaldehyde
-
in your system.
-
So, let's look at the next slide,
and basically this is just showing you
-
that you can have two set of this genes
that work fine, then you should be able
-
to break down your acetaldehyde
without a problem, but you could
-
also have just one gene that is
working properly and the other one
-
in inactive form, then you'll get
some flushing, but you might
-
be able to tolerate alcohol okay,
and then you have subset of people
-
who just totally have inactive form
of acetaldehyde dehydrogenase,
-
then they are basically not able
to break down acetaldehyde further,
-
and they will have severe reaction
to drinking alcohol.
-
So, by utilizing or capitalizing
on this mechanism, there is actually
-
a drug treatment that taps into this, and
it's disulfiram, brand name is antabuse,
-
and basically it artificially inhibits
the acetaldehyde dehydrogenase activity.
-
So, basically what it's doing is
it's inhibiting the enzyme to break down
-
acetaldehyde. So, if you drink alcohol,
you basically become extremely sick,
-
and this is one treatment option for
people who are addicted to alcohol, right?
-
So, by basically literally making them
physically sick when they drink alcohol,
-
it is a deterrent for them
to abuse alcohol.
-
Okay, let's talk about tolerance.
-
You develop tolerance to alcohol through
every mechanism that is known to us.
-
So, when we were talking about
Intro to Pharmacology, I told you about
-
three mechanisms that can be responsible
for tolerance development.
-
So, number one is metabolic tolerance;
the moment you take a certain drug,
-
your body becomes really efficient
at getting rid of it, so that happens
-
with alcohol.
-
The other one is
pharmacodynamic tolerance,
-
or functional tolerance, basically,
this is a tolerance that happens
-
because of the action that happens
at the receptor side or the synaptic area,
-
so it's at the molecular level.
-
The other one is behavioral tolerance;
in fact, I used the drop
-
in body temperature in response
to alcohol as an example to explain
-
what behavioral tolerance is.
-
Now, in addition to those three,
there are two other tolerance phenomena
-
that I need to talk about.
-
One is acute tolerance, and this
pretty much really only happens
-
with alcohol, I think, and this happens
within the course of a single ingestion,
-
or one episode of alcohol ingestion.
And then what happens is,
-
you develop tolerance, you sort of
develop -- You feel less affected
-
by the alcohol as time goes on,
and that is completely independent
-
of how much alcohol you have
in your blood system.
-
So, look at the graph on the right.
What that is showing you on the y-axis
-
is blood-ethanol concentration,
so how much ethanol is still circulating
-
through your body, and then
it shows ABCs,
-
so it basically shows you three
consecutive consumption of alcohol,
-
and then as the subjects are sitting there
over six hour period, the researchers
-
are asking them periodically,
"Do you feel intoxicated?"
-
And so, when they say,
"I feel intoxicated,"
-
they made a note, right?
So that's the time point between
-
hour one and two, and then you just
keep on asking them, "How do you feel?
-
Do you feel intoxicated or
do you feel sober enough?"
-
and then they make a note.
So, when they said, "I feel sober,"
-
they made a note, and that's
in hour six.
-
So, from this subjective feeling,
they are saying, "I feel intoxicated,"
-
about 1.5 hours into this experiment,
and then at sixth hour,
-
they feel totally fine,
"I can go home, I can drive," right?
-
But look at
the blood-alcohol concentration.
-
It is actually higher at sixth hour
when the subjects are saying
-
they feel sober, and this an example
of how you can develop acute tolerance,
-
so within a single sitting, basically,
independent of what's happening
-
at the physiological level, you develop
tolerance and you feel fine.
-
Now, cross-tolerance is --
So, cross-tolerance will pop up
-
in other substances to, and basically,
what that means is you actually
-
develop tolerance to another drug
as a result of developing tolerance
-
to the drug that you're
currently exposed to
-
and it usually happens within or among
drugs that share same mechanisms or
-
they are under same category of drugs,
so if you develop tolerance to alcohol,
-
the chances of you already having
some tolerance to other sedatives
-
or other CNS depressants
is pretty high, so things like
-
benzodiazepines or barbiturates
that all share same mechanisms,
-
you will have already developed
some tolerance, so the significance
-
of this, or the practical outcome of this
is that, let's say, you have developed
-
significant tolerance to alcohol,
and now you have to be prescribed
-
some kind of medication this is
benzodiazepine-based,
-
you will likely have to adjust your dose
and probably increase the dose much higher
-
than somebody who may not have developed
significant tolerance to alcohol.
-
Okay, and then there is also
this relationship between tolerance
-
and withdrawal, so our body's always
trying to maintain a homeostatic range,
-
and if something happens to our body,
let's say if there's sort of
-
external event, external force that is
changing how our body is currently in,
-
the rest of the physiological mechanisms
will try to compensate, and it will try
-
to basically bring our body back
to the way it should be, so
-
it's sort of counteracting whatever
external force is being exerted
-
onto the body.
-
So, let me walk you through this.
-
So, we'll go through
in the sprial arrow way.
-
So, we start with the initial state
where everything's well-balanced,
-
and then we take alcohol,
we ingest some alcohol.
-
I told you it's a CNS depressant, so
you see sort of this scale going down,
-
simply just representing some
state of over-CNS depression,
-
so our body is going to try to compensate
this by basically giving a little more
-
excitation, putting up a little more
excitability from your nervous system,
-
so you go back to sort of this
homeostatic range,
-
and that is indicated here as
a tolerant state.
-
Now, at that point, if you take
the drug out of your system,
-
or if the alcohol leaves your system,
what you will end up is,
-
you have this over-excited nervous system
that was trying to compensate
-
for the presence of alcohol, so now
the scale tips the other way, so that
-
the excitation, or over-excitation,
of your nervous system is the state
-
that you are in.
-
That's one of the reasons
why you have hangover.
-
If you've consumed significant amount
of alcohol the night before --
-
some of you have had this experience
the next day --
-
you feel pretty lousy, right, and it takes
a while for you to feel, come back
-
to normal state, and so that takes
a little while, but eventually,
-
we'll come back to normal state.
-
Now, that happens even at, even when
you're not addicted to something.
-
So, I know this graph is kind of
talking about it in terms of
-
if you are dependent on certain drugs,
but even if you are not dependent
-
on something, this type of balancing
and counteracting whatever
-
is in our body happens, but you can
imagine this happening in
-
more severe cases when you are
dependent on it, right,
-
and that your body is not actually
able to overcome this over-excitation
-
without the presence of alcohol,
so then you get this really severe
-
withdrawal symptoms, and the only way
for you to really come back
-
to normal state at that point is
to consume alcohol again,
-
which then will bring the balance
back into the homeostatic range.
-
Okay, so, in the next slide,
I don't really need you to remember
-
any of this, i think, but this is just
to highlight what happens when you're
-
going through this withdrawal state
after chronic alcohol abuse.
-
So, if you're trying to go cold-turkey,
and you --
-
So, this particular study was done
with people who have been consuming
-
10 to 15 drinks per day over 10 days,
so it's actually a significant amount
-
of drinking.
-
I actually figured out that a bottle
of wine contains about 5 drinks,
-
so that would be like drinking
2 to 3 bottles of wine everyday
-
for 10 days, so that's a lot of drinking.
-
And then they've monitored people
as they come out of this state,
-
so at the end of 10 days, this is
what they were observing as people
-
are going through withdrawal state.
-
We start with just being anxious,
agitated, and then you start having
-
some sleeping issues, but then
you also start having actual
-
motor issues, so there might be tremor,
and then it starts to affect
-
your cognition, so you could be
disoriented, sometimes you actually have
-
seizure episodes, you have convulsion,
and then the really final stage,
-
here it is noted as delirium tremens,
and the reason that I have a bunch of
-
pink elephant on the left is because
a long time ago, somebody who was
-
going through this withdrawal state
was writing down all the things
-
that were happening to him,
and he was hallucinating pink elephant
-
in the room, so there's really
nothing cute about pink elephant.
-
It kind of symbolizes this
severe withdrawal from alcohol.
-
And if not done properly, you can actually
die from some of these convulsions
-
and some side effects.
-
With chronic alcohol abuse, you can also
actually have brain damage.
-
So, in this slide, you will see
on coronal sections of
-
actual brain imaging, so the picture
on the left is taken from somebody
-
who has been abusing alcohol
for a long time,
-
and the right is a control brain, right,
and then the pictures below
-
are basically 3D image of these
actual human, actual imaging,
-
and they've costructed what the cortex
basically looks like, and you see
-
a lot of atrophy, or basically reduction
in brain mass in this person
-
who's been abusing alcohol
for a long time.
-
So that can actually happen.
-
And it can happen because of
various factors:
-
the alccohol itself,
the elevated acetaldehyde
-
that I said was highly toxic,
also liver -- I'm not talking about
-
liver issues here, but the liver
is getting hit really hard,
-
and oftentimes people who abuse alcohol
also really don't eat properly,
-
so that's another huge factor, in fact,
there is actually a brain disease
-
called Korsakoff syndrome, and
the actual cause of Korsakoff syndrome
-
is deficiency of thiamine, vitamin B_1,
but at least in United States,
-
the main cause of Korsakoff syndrome
is alcohol abuse, and that's partly
-
because for some reason, alcohol
actually prevents the,
-
or at least impairs the body
to fully use thiamine as a nutrient,
-
but also because people don't
eat properly, so they have an
-
over-inadequate nutrition, and if you
have very low thiamine, it can actually
-
start affecting your nervous system
and various other things,
-
and it can actually show up as a,
initially, some confusion, disorientation,
-
but eventually it will progress
to memory loss and cognitive deficit.
-
Okay, there's also fetal alcohol syndrome,
and that's when the pregnant woman
-
is exposed to high levels of alcohol,
and that's because the alcohol
-
can cross placenta really readily,
and this actually, especially if
-
the pregnant woman is exposed
to alcohol at early stage of pregnancy,
-
so somewhere between four and nine weeks
of pregnancy, that's when it affects
-
the fetus the most.
-
And the problem with this is,
or the really sad thing about this
-
is that most women do not know
that they are pregnant during that time,
-
so if you have someone who already
abuses alcohol quite a bit or
-
who drinks alcohol quite a bit,
by the time they realize that they
-
are pregnant, it might be already too late
in terms of how much alcohol has affected
-
the fetus, and there are all these other
symptoms including: low birth rate,
-
physical abnormalities, and also
including the brain function.
-
So, and then, one of the unique things
is that it also affects the formation
-
of their face or cranial facial formation,
so let's look at the next picture.
-
So, that's sort of a -- the top left
picture is a typical, I guess,
-
formation that you see in a child
who has fetal alcohol syndrome,
-
and the picture below is actually
a animal model that tries
-
to copy or mimic this
fetal alcohol syndrome
-
so that we can study what is going on
in the nervous system, and the animals
-
also show similar facial formation
as human, and then one thing
-
I just want to point out,
at least in this model,
-
you see that there's a complete
elimination of olfactory bulb
-
which is shown by the arrow,
and then the overall cortex
-
seems to be a little smaller too.
-
On the right side, we have some
brain scans of individual kids,
-
the number represents the age,
and M or F represents
-
male or female; the very top row
is a kid who doesn't have
-
fetal alcohol syndrome, so that's
what it's supposed to look like,
-
and then the three subjects
have varying degree
-
of fetal alcohol syndrome.
-
And one thing that I just
want you to take away from this
-
is that we can't really say,
If you have fetal alcohol syndrome,
-
"these are the brain structures
that are affected, and this is
-
how the outcome is going to be."
There seems to a lot of variations
-
and kids are affected differently.
-
The one example being, if you look at
the brain with red arrow, there is
-
sort of an abnormal formation
of corpus callosum;
-
corpus callosum is the white fiber that
connects the left and right hemispheres,
-
and it looks like a C that's been rotated
90 degree highlighted with white color,
-
but if you look at the brain
all the way at the bottom,
-
pointed by the yellow arrow,
you see shrinkage of cerebellum,
-
so again, effect of alcohol on fetus
seems to vary quite a bit.
-
Okay, there is also some
beneficial effect of alcohol.
-
It generally seems to apply
to older people,
-
and one of the reason that
it might be beneficial
-
is that it can work as vasodilation,
or dilator.
-
So, basically, the idea is that it allows
the blood to flow a little better,
-
and that can actually help some
cognitive function or even
-
vascular function in some older adults,
but we're talking very moderate amount
-
of alcohol drinking.
-
Okay, I think that's all I want to say
on this slide.
-
So, ah, okay, so, if you need
to take a break, now is
-
a good time to take a break,
because now we are going to dive
-
into the neurochemical effects
of alcohol, and I'm going to talk about
-
various neurotransmitters that
the alcohol influences.
-
Okay, so, alcohol influences
a lot of neurotransmitters,
-
or neurotransmitter systems.
-
This particular picture separates
what's considered to be non-specific
-
alcohol effect and
specific alcohol effect.
-
The nonspecific alcohol effects are
basically how the alcohol can disrupt
-
your cell membranes, including
blood-brain barriers,
-
and because the alcohol can diffuse
through these cell membranes,
-
sometimes repeated exposure or
heavy exposure to heavy concentration
-
of alcohol can mess up with
the structural integrity
-
of the membrane, but I'm really
not going to talk about that.
-
I'm going to talk about
what's consider specific effects,
-
meaning how the alcohol targets
different receptors and different
-
neurotransmission.
-
The alcohol works as glutamate antagonist;
if you are exposed to it for
-
the first time or if you're not
really abusing it.
-
So, it will block especially
NMDA receptors, so we talked
-
about NMDA receptors being different
from the other ionotropic receptors,
-
such as AMPA and Kainate,
so it primarily works
-
as an NMDA antagonist, but
if you are repeatedly exposed to alcohol,
-
basically, if you abuse alcohol,
there's going to be some up-regulation
-
of NMDA receptors, and I think
I've told you this at some point,
-
that's what our body does.
-
Let's say, if you are bombarding
the synaptic area with
-
some sort of agonists, the receptors
are going to try to down-regulate,
-
basically not respond to the agonist
as much, and the opposite happens too.
-
If you bombard the synaptic area with
some kind of antagonist, then
-
the receptor is going to try to maximize
whatever's around, so that it can respond.
-
So, basically, that's what you're seeing.
Because alcohol inhibits an NMDA receptor,
-
if you do that continuously
or over a regular time,
-
what the NMDA receptors are going to do
is up-regulate now.
-
That's okay if you have alcohol
in the system, you are still maintaining
-
some homeostatic state.
-
But imagine what happens if
you try to go cold-turkey, right?
-
So you have been abusing alcohol,
which means you pretty much
-
have alcohol on board almost
all the time, now if you try
-
to stop drinking, all of the sudden,
you have all this up-regulated
-
NMDA receptors, and what is it
going to do, even just regular functioning
-
whenever there's some glutamate released
is going to respond to glutamate
-
a lot better and more efficiently
than they need to in a regular system.
-
And that's how you could end up with
hyper-excitability of your nervous system,
-
your brain, which then can cause seizures,
because you have too much excitation
-
going on, and the unique thing
about NMDA receptors is that
-
it can let it calcium ions
as well as sodium ions, right,
-
and I told you very early on that
as much as calcium is important
-
for our regular cell-signaling,
too much of it is very, very toxic
-
for our cells, so if you have
a lot of calcium coming into the cells,
-
you can also cause cell death.
-
That can also be responsible
some of the brain damage that you see
-
in people who abuse alcohol.
-
Okay, this is an example of
basically what I just said,
-
so it's an evidence, so you will
believe me or you know
-
I'm not just making this up,
so this is -- They measured
-
over dopamine output
or dopamine level or release
-
in the striatum in animals
that are going through,
-
currently going through withdrawal.
-
So, these rats have been exposed
to a lot of alcohol, to the point
-
where now their body is dependent on it,
and then they stop receiving alcohol.
-
So, let's look at the graph
on the top left with the line graphs,
-
and that is showing you
over glutamate release, or output.
-
And basically, there are some
other groups, but what you want
-
to note is the graph that is,
the line graph that's going high,
-
basically, that's the glutamate level
that you get from animals
-
that are going through
the withdrawal right now.
-
And then the bottom bar graph is showing
you over withdrawal severity,
-
so the experimenters, there are
various behavior measures
-
that you can do to see how severe
the withdrawal is for the animals,
-
and basically, you are looking at
time dependent withdrawal being,
-
and that basically lines up with
the level of glutamate you see,
-
so around 12 hour time, from the time
of stopped receiving alcohol,
-
you get most severe withdrawal output,
and that's also when you see
-
very high level of glutamate increase
in the striatum.
-
And then finally, the graph in the middle
is just showing you the correlation,
-
so the y-axis is showing you
over withdrawal score
-
and the x-axis are showing you
over glutamate output,
-
and so these are individual data point,
so if the animal didn't show a lot of
-
withdrawal score, you also see that they
didn't have a lot of glutamate output.
-
The animals that showed really severe
withdrawal symptoms also had
-
very high levels of glutamate output,
so this is one piece of evidence
-
that supports that this increase
in glutamate output might
-
be responsible for some of
the withdrawal symptoms
-
that people experience.
-
So, let's finally talk about GABA.
-
Just like how alcohol influences
glutamate, sort of at the initial state
-
versus over repeated use,
something similar happens to GABA.
-
First, alcohol is a non-competitive
GABA agonists, so the presence of alcohol
-
will increase the function of GABA,
and that's why it is CNS depressant,
-
because GABA is the major inhibitory
neurotransmitter, so when you engage
-
in GABA system, you basically let
chloride ions go in, which causes
-
hypopolarization, right, and that's how
you end up with inhibitory output.
-
So, basically, what alcohol does
is it enhances the flow of chloride ion
-
into the post-synaptic cell,
so you are helping the GABA
-
do its job better, but again, if you are
exposed to alcohol over and over,
-
or if the alcohol is in the system
over and over, what will happen is
-
the GABA is going to try to down-regulate
its function, so you go from having
-
this enhanced GABA function over
the influx of chloride to basically
-
reducing the chloride inflow further from
even the baseline, so you reduce
-
the GABA function.
-
And think about what will happen
if you have an over-reduction
-
in inhibitory mechanism, you are basically
allowing your nervous system's
-
excitatory output to go without
proper check, right?
-
When we are talking about
glutamate and GABA,
-
I said you need to have sort of
this ying and yang of excitation
-
and inhibition being in check.
-
Now, with repeated exposure
to alcohol, you basically have
-
malfunctioning inhibitory mechanism.
-
And then in the previous slide when
I was talking about glutamate
-
I said, independent of this GABA
function alcohol can also basically
-
increase glutamate activity
so you have sort of this
-
two really bad situation
occurring at the same time.
-
You are enhancing this excitation
of the nervous system
-
while you are inhibiting
the inhibition system.
-
Your brain is very vulnerable to
going into this excitatory drive
-
and that's partly why you can
get seizures when you're going
-
through severe withdrawal stage.
-
The other neurotransmitter system
that is involved is dopamine.
-
Dopamine is going to show up
over and over in other substances.
-
Partly why, this will not be a substance
of abuse if dopamine is not involved.
-
Why? Because in order for you to
have this positive reinforcing effect,
-
this euphoria effect from this drug,
which then encourages you to take
-
the drug again, you need to
have dopamine involved.
-
And that's one of the first thing
that we figure out,
-
whether the drug has
positive reinforcing effect, right?
-
Do animals self-administer?
-
We know that dopamine is very important
for the self-administration part.
-
Any drug that is consider
sort of abusive drug,
-
you will see some involvement of dopamine.
-
Whether it works directly on
the dopamine receptors,
-
or not, there's sort of this indirect
way of influencing them too.
-
So you basically get enhanced
dopamine activity
-
in presence of these drugs,
especially at the beginning
-
when you're first being exposed to it.
-
And these graphs are basically
showing you this.
-
The one on the left, the line graphs,
are just two different types of rats,
-
the "Wistar Rats" is type of rat strain
and "P Rats" here is actually,
-
rats that are derived from what
we call "selective breeding".
-
So they happened to find some
individual rats that seemed to
-
drink a lot more alcohol than
their counterparts.
-
If you'd only select those rats, and
breed them over multiple generations,
-
you basically end up with a bunch
of rats that prefer alcohol
-
and that's what "P" stands for.
-
Anyway these rats show very
high increase of dopamine.
-
The one on the right, the bar graph,
the middle and the one on the right
-
are animals who've received
dopamine antagonist into
-
their nucleus accumbens so this
is a case where the dopamine
-
is not working properly in
the mesolimbic pathway.
-
And then they're looking at
the over-response to ethanol.
-
As you can see, they do not
respond to ethanol as much as
-
a control group that has
intact mesolimbic pathways.
-
So just highlighting the importance
of dopamine here.
-
I think the next one is opioids, yes.
-
The next lecture is entirely on
opioids, things like morphine,
-
heroin, and fentanyl.
-
Why am I talking about opioids here?
-
It turns out there is actually tight
relationship between alcohol and--
-
let me rephrase it, alcohol can also
influence opioid system,
-
and you can also manipulate
opioid system to regulate
-
overall alcohol consumption behavior.
-
Kind of like glutamate and GABA,
if you are exposed to alcohol
-
for the first time or not
in a repeated fashion,
-
you increase the opioid activity
and one of the outputs is
-
increase in endorphins.
-
So endorphin is an endogenous
opiate substance.
-
You guys have probably heard
of endorphin,
-
some marathon runners will say
when they run, they think they
-
release endorphin which then
sort of blunts some of the
-
muscle pains or some of the pains
they might get, or some will say
-
this is responsible for some of
the highs they get, sometimes
-
they call it "runner's high".
-
Anyway this is something that
our body naturally makes,
-
and opioid system is heavily
involved in blocking pain
-
or regulating pain so endorphin is
kind of like the natural pain-killer
-
our body's capable of making.
-
When you're exposed to alcohol,
your endorphin goes up,
-
also contributing to sort of this high
or euphoric effect that you get
-
from taking alcohol.
-
Again, if you are exposed to alcohol
chronically and you abuse them,
-
it seems that the opioid system
generally-- or the activity goes down,
-
including reduction in
endorphin production.
-
Now the graph is showing you
something slightly different,
-
they are using Naltrexone,
which is an opioid antagonist,
-
and to see it's effect on
alcohol self-administration.
-
In the previous study I showed you how
you can inject dopamine antagonist,
-
and that also reduces response to alcohol.
-
In this case they were injecting
opioid antagonist, and again,
-
there seems to be some reduction
in self-administration,
-
and you see a dose-dependent
response, meaning if you received
-
the highest dose in this study, your self-
administration behavior was the lowest.
-
Finally, one other substance or
neuromechanism that I want
-
to talk about with alcohol is CRF,
corticotrophin releasing factor.
-
This is kind of like a hormone
that is involved in our body
-
responding to stress but it is
also used centrally,
-
meaning used by your brain.
-
And our brain is capable of
producing CRF, as well,
-
and it is especially used by the amygdala,
I know I wrote down a very detailed
-
brain name, so the central amygdala/
bed nucleus of the stria terminalis,
-
we are just going to remember them
as the amygdala, and then I talked
-
about in the previous lecture how
there is this sort of change in
-
neurostructure that goes or--
neuromechanisms that go from
-
relying on the mesolimbic pathway
to the amygdala pathway kicking in
-
as you go from non-dependent use
of drug to dependent use of drug.
-
And we know the CRF goes up
as you go from taking alcohol
-
occasionally to when you start
abusing alcohol.
-
We know that CRF plays an
important role in sort of
-
this alcohol-addictive behavior.
-
Here is just another study that
highlights what I just said,
-
they are now looking at the
level of CRF in the amygdala,
-
and the graph on the left is showing
a comparison, what happens to
-
the CRF when the animal is going
through some sort of stress event.
-
Because that's what CRF
is really known for.
-
In this case the animals are basically
restrained, for about 20 minutes,
-
they don't like to be restrained
so it's a mild stressor,
-
and you see the level of CRF
going up, right?
-
And then the one in the middle,
is the increase of CRF
-
as the animals go through
withdrawal stage.
-
So another set of animals will
have been exposed to ethanol
-
over and over so now they are
sort of physically dependent
-
on ethanol, and then they
stop receiving ethanol.
-
And then what you are seeing
here is this gradual rise of CRF,
-
and so we think that increased level
of CRF also contributes to some of the
-
adverse effects or adverse symptoms
you get when you are going through
-
a withdrawal stage.
-
Let's talk about alcohol use disorder
and some of the treatments,
-
some of the contributing factors
and the treatments that go with it.
-
In order to diagnose somebody
with alcohol use disorder,
-
a lot of things need to be
taken into consideration,
-
like the frequency and pattern of use,
-
binge drinking itself is doesn't--
if you are engaged in binge drinking,
-
it doesn't necessarily mean that
you have alcohol use disorder,
-
but binge drinking itself is also a
problem especially young people
-
like your age group.
-
There are a bunch of diagnoses that need
to happen to diagnose this disorder.
-
But that part I'm not really
going to talk about.
-
Let's talk about some of the contributing
factors that go into alcohol use disorder.
-
In the next slide, we call this--
it's the three-factor model,
-
and I've talked about some of these
factors sort of in the broad term
-
when we are talking about
different factors contributing
-
to addictive behavior, right?
There's the psychological factors,
-
and there's sociocultural factors,
and biological factors.
-
Let's first talk about psychological
factors in the next slide.
-
One of the things that is heavily
linked to people who abuse alcohol
-
is sort of over anxiety level.
-
We think that one of the things
that alcohol alleviates is
-
sort of your stress levels.
-
When you're facing with a lot
of stressors in your life,
-
alcohol can have reinforcing effects
and then you can sort of--
-
make you feel a little relieved
from the stress and the tension.
-
There is a high level of lifetime anxiety
among people who abuse alcohol,
-
also if you take people who abuse
alcohol there's a significant number
-
of people who dealt with a major stressor
in their early life, to put it the other
-
way around the major stressor in early
life is a risk factor for developing
-
alcohol abuse disorder later in life.
-
In the next slide let's talk about
some of the neurobiological factors.
-
One thing that this particular
study it's suggesting, is
-
if you react to alcohol not as much
as some other people,
-
maybe your chance of developing
alcohol use disorder is greater,
-
so low sensitivity to alcohol.
-
But that really only is within
the people who have parents
-
who already have alcohol use disorder.
-
In this particular study they've only
taken sons of parents who have AUD,
-
alcohol use disorder,
and then they've just
-
looked at their reaction to alcohol,
so their subjective high,
-
which is the top graph, and
their sort of motor reaction,
-
motor response to alcohol,
so in this one a sway score.
-
They've looked at people who
later developed alcohol abuse--
-
later who abused alcohol
versus who didn't,
-
they see a difference in their
baseline response to alcohol.
-
That might be some neurobiological
contributing factor.
-
In the next slide I think I talk
about some genetic components.
-
Yes there's some heritability,
if you have parents who have
-
abused alcohol the advice is that
you try not to be exposed to alcohol
-
because your chance of developing
the same disorder is pretty high.
-
The concordance rate among identical twins
is higher than fraternal twins,
-
so fraternal twins are the twins who don't
really share the same genetic make-up
-
whereas the identical twins do.
-
The concordance rate basically means
if your twin has a particular disorder,
-
what is your chance of having
the same disorder?
-
It is much higher among identical twins
in terms of the alcohol use disorder.
-
And then there are this bunch of genes
that show that might be linked to
-
alcoholism but like I said
in the previous lecture,
-
we can't really pinpoint a particular
gene or even a set of particular genes
-
and say "Hey, if you have variations
in these genes then we know
-
what your chances of developing
alcoholism is."
-
So we are not quite there.
-
And oftentimes, and also we've
talked about epigenetic mechanisms,
-
so even if you have some of
these genes, if you're in a--
-
if you can control your environment
where those genes are not fully expressed,
-
then your chances of developing
the particular disorder might
-
also go down significantly.
-
Okay, so let's talk about treatments.
-
This is the last slide of the lecture.
-
First, you have to go cold turkey,
or you have to basically detox,
-
you have to go through a
detoxification process,
-
before you can receive some
sort of long-term treatment.
-
And as you saw earlier, the withdrawal
stage, from alcohol abuse can be quite
-
bad, and you actually go through
really severe physical reaction
-
as you try to detox from alcohol.
-
One drug that can be useful during that
process so that you don't have all this
-
really severe bad symptoms,
to the point where it can be
-
actually a danger to your health,
is the use of benzodiazepine drug.
-
So things like diazepam,
we also know them as Valium,
-
because they are targeting
the same GABA mechanism,
-
so alcohol, benzodiazepine are both
non-competitive GABA agonists.
-
Basically instead of having alcohol,
you are basically having benzodiazepine
-
still influencing the GABA system so
that you can gradually reduce this
-
without having the alcohol being
in the system so that's one thing
-
that is used during detoxification stage.
-
And then once you've gone through
the withdrawal stage successfully,
-
you kind of need to be on some
sort of long-term treatment plan.
-
There is definitely cognitive
treatment that can be done,
-
and behavior therapy that can be done,
but in terms of drug treatment,
-
there are two things that
are currently used most,
-
one is Disulfiram, I talked about this
earlier when we were talking about
-
the metabolic process, so this is
the inhibitor of the enzyme
-
the acetaldehyde dehydrogenase
that is supposed to break down
-
acid aldehyde so it physically makes
you sick when you drink alcohol
-
if you have this drug on board.
-
The other one is Naltrexone,
so I talked about this when
-
we were talking about opioids'
involvement in alcohol processing,
-
because of the alcohol's influence on
opioid, if you give them opioid antagonist
-
it seems to reduce their craving for
alcohol, so the graph down here
-
is showing you, this survival rate
in a way, so the percentage of
-
people who are not relapsing,
so who are still staying on-course,
-
so the higher number the better, right?
-
The group that is receiving Naltrexone,
with behavior therapy are staying
-
at the end of 12 weeks of therapy about
70% of the people are not relapsing
-
whereas the group in the blue line
are going through behavior therapy,
-
cognitive therapy without Naltrexone,
and at the end of 12 weeks only about
-
30% of people have not relapsed.
-
So there's a significant difference
with the use of Naltrexone.
-
Okay so that is all I have
to say about alcohol,
-
in the next lecture we'll
talk about opioids.