https:/.../2020-07-15_psy353k_alcohol.mp4

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.