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.