drugs and brain
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Introduo
Hello. Welcome to Coursera. Welcome to the California Institute of Technology, Cal
Tech. My name is Henry Lester. I'll serve as the instructor for this course on drugs
and the brain. We're going to start with two modules, each about six minutes long.
These are introductions, and so there won't be, there will be no assessments
after these two. Introductory modules. I'll show you the kinds of images that
we'll, we'll be using, the kinds of concepts we'll be using, and the kind of
pace that we will be using. we'll be learning some pharmacology, of course, a
bit of neuroscience, not so much as I would like to teach you, but there will be
other courses on that. Some biochemistry, some biophysics, and of course, a little
bit of disease orientation. So let's get started with this first module. An overview like some
basic science. First we'll ask what is a drug, and we'll give four examples. We'll give as an
example nicotine, the addictive drug from tobacco. We'll be coming back to nicotine and the
nicotine system fairly often in this course, because it is the research of my laboratory. And I'm
interested both in nicotine as an addictive drug and also in the fact that people who use.
Tobacco for many years seemed to have a lower, not a
higher, but a lower incidence of
Parkinson's disease. Then we'll talk about
protein. during our first, introduction to
what's a drug, a local anaesthetic, a
synthetic one. We'll discuss more theme. a
pain reliever which is also addictive
during our first module on what's a drug.
And during our module on what's a drug
we'll also talk about botulinum toxin.
Botulinum toxin may be one of the first of
the protein drugs that can be used on the
nervous system and we'll discuss its
advantages and its many uses these days.
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Of course, drugs in the brain also
requires us to talk about the brain. as we
mentioned, I'll introduce just a bit of
neuroscience. for instance the
relationship between the brain and the
spinal cord, in the central nervous
system. Some of the terms we use to
discuss the brain, and some of the basic
concepts. We'll talk about large scale
circuits of neurons, small scale circuits
of neurons, nerve cells. The contact
between individual neurons. The little
chemical hop from a pre-synaptic neuron to
a post-synpatic neuron. We talk this
little chemical hop the synapse, of
course. I'll remind you that an adult
brain contains about ten to the eleventh
neurons, 100 billion neurons, and each of
these might receive about 1000 synapses a
piece, for a total of about ten to the
fourteen synapses. Nearly all of these
form during the first two years of life.
And so a fetus and an infant is very busy
making about a million synapses per
second. No wonder they get so tired. Then
of course we, we'll talk about drug
receptors. I'll remind you that most drug
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receptors are membrane proteins. Here is
our example. the nicotenic acetone coleine
receptor. It has a region where drugs
bind, a region that goes through a
membrane, and a region that has a, that
expands into the plas, into the cytosome.
Down here at the bottom of the slide is a
length to a database at the NIH, the
National Institutes of Health, which will
give you a three dimensional structure
that you can manipulate yourself to
understand the basic. Parts of a protein
and the basic structural themes. we'll be
posting slides that have URLs on them on
the course website, so that you can follow
these URLs yourself without any further
work. in terms of drug receptors being
membrane proteins, and again here the
nicotine receptor. Here is actually the
best resolution we have of the binding a
nuclear molecule binding to its receptor.
And then we'll go on to talk about the
link between binding to a receptor and
activating another part of the receptor.
Here, we will talk about activating a
channel. Of course we'll do this for
receptors in addition to this example, the
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nicotinic acetylcholine receptor. An
important other aspect of drug action on
ion channels is the fact that drugs block
ion channels, in many cases literally,
like a plug in a drain. Here is a .
To skim cartoon of these single channel
recording. We'll mention single channel
recording briefly. And we'll discuss the
fact that when the plug is in the ion
channel it doesn't conduct, but when the
plug is out the ion channel conducts as
usual. We'll talk about how sometimes
these plugs get stuck in ion channels, and
that's the basis for anti-epileptic drugs
and for anti-arrhythmic drugs in the
heart. Having talked about IN channels,
we'll, and a little bit of electricity,
we'll then go to an important part where
we discuss drugs acting on G protein
pathways. The G protein coupled receptor
is a bit more complex as a. Pathway than
IN channels. We have the receptor itself,
with seven transmembrane helices. We have
the G protein. We have the effector for
the G protein. We'll spend some time
discussing several aspects of this
pathway, because it has several different
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types of, of the action in the brain. And
then we'll talk about how to measure the
intracellular effects of G protein coupled
receptors, and of the ion channels. We can
measure some intracellular effects using
advanced microscopy, live cell imaging,
usually with fluoroscence. And we can
measure other effects using biochemistry.
I'll stop here and let you absorb this
material. I do want to remind you to see
two items on the course website. The first
is my sources of research funding. A
professional would call this my
disclaimers. and the second disclaimer is
about medical advice. You should not take
medical advice from me or infer that I'm
giving you medical advice, and you should
not use this course to give medical advice
to any friend or family member. See you in
a little while when we go to the second
introductory module.
Hello. Welcome back to drugs and the brain
at Caltech and Coursera. This is Henry
Lester at Caltech and, just to prove it,
here is my Cal-tech pocket protector. and
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I'll just stick it right back here in my
pocket for the rest of today's session.
And it will be there most times, most
days. We're going to talk mostly about
diseases in this brief introductory
module. Reminder that there will be no
assessments after this module, but from
the next one on there will be assessments.
The first topic is, that drugs act on
transporters. In particular,
neurotransmitter transporters. Two often
used classes of drugs these days, are
first of all drugs that act on the sodium
coupled citoplasma membrane or cell
membrane: serotonin transporters. Drugs
that act on the serotonin transporters are
both drugs of therapy and of abuse, the
therapeutic drugs or the serotonin
selective reuptake inhibitors or SSRI's.
They are antidepressants, and they have
trademarks that we are all, familiar with.
And they block the uptake of serotonin,
mostly into presynaptic nerve endings.
Another class of neurotransmitter
transporter blockers, also have uses both
in therapy and in abuse. These are
the Dopamine transporter blockers. Here is
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Dopamine. These transporters
are also expressed on pre synaptic nerve
terminals. They are also sodium coupled.
They have trademarks that are familiar to
us and there are other drugs that work
on these Dopamine transporters that are drugs
of abuse,such as Cocaine and Amphetamine.
this will put us in a position to
understand all of the major classes of
recreational drugs. Now the recreational
drugs are not necessarily drugs of abuse.
a very familiar recreational drug is
caffeine, and I may be partaking
of this recreational drug from time to
time during our course. I'll have a little
sip now. in addition we'll be talking
about LSD, morphine and heroin,
tetrahydrocannabinol, THC, cocaine, PCP or
phencyclidine and of course nicotine, the
topic of my research. So this will be our
constellation of recreational drugs and
we'll spend a couple of modules talking
about how they work on each of their
target molecules : their receptors. We'll
move to the topic of drug dependence or
addiction, and we will use those terms
more or less independently. We'll talk
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about the major components of addiction
and
dependence. First tolerance and then
dependence, and goal seeking behavior.
Tolerance means that an organism becomes
less sensitive to the drug as time
goes on, and dependence means that an organism cannot
function normally without that drug, and
goal seeking behavior means that the
organism tries to get that drug. we'll
discuss the metabolic and cellular
mechanisms of tolerance. again using as an
example nicotine addiction we will talk
about the various components of an
addiction. The fact for instance that
nicotine gives a sense of well being but
also some nicotine addicts believe that
they think better when they smoke and
that's called cognitive sensitization.
Some people smoke for stress relief, some
people smoke because they are fairly sure
that if they stop smoking, they're going
to gain ten to fifteen pounds in the first
year. And some people smoke and get
nicotine in order to self-medicate. So the
question becomes in every case of drug
abuse and dependence : what are the changes
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in the brain during chronic exposure to
that drug? And we'll try to address some
of those questions during this course. in
order to address these questions we have
to go all the way from genes, through gene
expression RNA, through proteins, through
the differences between the exogenous
drugs (the ones that come from outside)
versus the indigenous (the natural
neurotransmitters), how the drugs bind to
their receptors, the intercellular events
that occur after cells bind repeatedly,
for days or weeks. Effects on neurons.
Effects on the junction between neurons,
the synapses. Effects on circuits of
neurons and finally effects on behavior.
so this is a complex topic. We'll t ry to
touch upon all of these topics during the
course. in particular we'll talk about how
activation of a G Protein coupled pathway
for prolonged periods of time, can lead to
changes at the level of genes and how
this can be hijacked by nicotine
receptors and by other receptors, that can
introduce intra-cellular messengers on
their own. This is thought to be a major
component of drug addiction. So here is a
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graph, schematic, of a pathway of the sort
I just told you about. Nicotine receptors
leading to intra-cellular transmitters,
and leading to gene activation. Now the
course is not going to emphasize nicotine
addiction to the extent that this
introduction does, but it's a convenient
way of tying the introduction together. So
then, we will be in a position to talk
about drugs for neural diseases and a
classical drug in that respect in use for
just about 40 years now is L-dopa or
levodopa. And we'll discuss how levodopa
gets converted by an enzyme. An enzyme is
a protein that's a catalyst from the
Greek, to leaven, as in, and the enzyme
that levels bread from yeast. We'll talk
about how this enzyme converts L-dopa to
dopamine itself. L-dopa does enter the
brain but dopamine does not. And so this
will give us an opportunity to
re-emphasize the important aspects of
blood brain barrier, and drug entry into
the brain. indeed parkinson's disease,
which is treated with L-Dopa, will be an
example for neuro-degeneration, and we'll
talk about that more than we talk about
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Alzheimers, or ALS. Parkinson's disease
involves degeneration of neurons that make
dopamine in a particular region of the
brain, the Substantia Nigra. We'll then
move on to drugs for psychiatric diseases.
We'll treat them as chemicals. We'll talk
about their permeation through membranes
and of course their targets. A major
question for psychiatric drugs is what
happens during the two to three weeks
that it takes between the time a person
starts taking a psychiatric drug and the
time he feels completely better. This is a
topic that is of great interest to me in
my present research and to all psychiatric
researchers as well. The answers are not
known. An exception is the novel
antidepressant ketamine, called on the
street Special K. Ketamine exerts it's
antidepressant effects within about two
hours. However, when used at higher doses,
Ketamine also causes hallucinations, and
many other kinds of unpleasant
behavior, so, this is an active field of
research for drug companies. Another
classical by now anti-depressant, is
fluoxetine, also known as prozac. This one
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is one of the psychiatric drugs that takes
two to three weeks to act. We'll also talk
about the anti-psychotic drugs, those that
are used primarily for schizophrenia as
well as for bi-polar disease. We'll
discuss the classical anti-psychotic drug
chlorpromazine. And its benefits and its
side effects and some newer classes of
psychotic drugs. The so called
atypical antipsychotics such as clozapine
whose trademark is clozaril. And of course
we'll be coming back to nicotine from time
to time too which is used by
schizophrenics to self medicate. A good
example of a patient with probable bipolar
disease was the painter van Gogh who had a
meteoric unfortunately short career and at
the end of that career, he did kill
himself. So, this will be our exemplar
bipolar patient. And one of our exemplar
schizophrenia cases will be David
Helfgott, the subject of the movie "Shine",
the great pianist, we'll talk about
his life and about his psychotic
episodes, all based on the book by his
wife, and we'll discuss the medications
that he now takes, again, according to the
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biography by his wife. We may also have
the chance to talk about another famous
psychiatric patient John Nash, who was the
topic of the movie "A beautiful mind".
Then, toward the end of the course we're
going to come back to this mystery about
what happens during the two to three weeks
that constitute the therapeutic lag: the
time that a patient takes before he feels
completely better. We'll talk about the
fact that contemporary ideas about
psychiatric drugs emphasized binding to
classical targets, but that an idea that
I'm very fond of called 'inside-out drug
action', emphasizes binding to the same
targets but actually within the cell, in
the endoplasmic reticulum, and the Golgi's system. Then we'll turn to this
interesting topic of developing new drugs
for the brain. And we'll talk about
Eroom's law, note that Eroom is moore
spelled backwards. Moore's law applies to
semiconductors and to computers, and
Moore's law basically says that it gets
cheaper by a factor of two every eighteen
months, a factor of ten every five years,
to do data processing. Well just the
opposite applies to drugs these days, and
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has applied to drugs for the last sixty
years. You can develop fewer and fewer
drugs per billion dollars spent on R&D
spending. This is a particular problem
with neural drugs. We'll talk about the
prospects for changing this process, and
perhaps one of you students, as a result
of this course, will be motivated to. Get
a new idea that changes the course of
Eroom's Law. So, I'll just remind you to
look at the disclosures on the course web
page and the disclaimer about medical
advice and, next time we'll talk about
what is a drug. Thank you so much.
Hello. In this session, we'll discuss more
about the nature of drugs as chemicals. In
particular, we'll talk about their
permeation, their entry into the nervous
system and into the brain, and then we'll
spend a few minutes talking about a
particular protein drug, botulinum toxin.
First routes into the nervous system.
Nicotine enters the nervous system, and
then the brain, via one of several routes.
It can be smoked, which is the way about a
billion people around the world get
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nicotine. it can be chewed, either as
tobacco leaves or as nicotine gum. And it
can enter through skin patches as well.
Many people use nicotine patches. As a way
to stop smoking which is an important
goal. Procaine and other local anesthetics
are generally injected into the sites
where one wants to dull pain. Dentists use
procaine a great deal, so do other
physicians. Some local anesthetics related
to procaine can also be put into creams,
for instance for sunburn relief, and in
the creams they can diffuse into the skin
and cause local pain relief. Morphine can
be smoked from the opium poppy. It can be
injected by the physician or by the drug
abuser. And, it is also fairly copen,
common to bring morphine into the body by
a suppository. So, each of these ways is
appropriate for morphine. And, finally
botulinum toxin. When used
therapeutically, it's usually injected
when one gets botulism, botulinum
poisoning. That's because one typically
eats food that's contaminated with
botulinum toxin. So, there are various
routes into the nervous system. Let's
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discuss permeation through membranes and
through lipid barriers. This is a key
concept in drugs in the brain. When eh,
we're going to treat a general drug, an
alkaloid, as having an R group and these
Rs can be many groups as we saw in
previously. so R is a general group and
we'll concentrate on the amine group. This
is a primary amine. NH2 group contained
within the drug. This is a neutral form of
the drug and we get the neutral form of
the drug by taking it in through the mouth
or the stomach o r the lungs as in this
picture here. Neutral forms of drugs are
quite permeable through lipids, through
fats, especially through the membranes.
And, so, typically neutral forms of drugs
go through membranes quite easily.
However, it is the active charged form,
which is usually the form that interacts
with the drug receptor. So the neutral
form takes up the proton, becomes
protonated, charged and this is the form
that interacts with the receptor. This
protonation deprotonation takes only a
millisecond or so and it can occur either
in the blood or the brain or it can occur
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outside the blood and the brain, in the
lungs, or the stomach, or the mouth. So,
that's a general statement about alkaloid
drugs and about synthetic drugs as well
that contain amines. And in general when
we have higher pH this tends to take the
proton off the charged form of the drug.
So, we have the neutral form of the drug.
And, so in general, higher pH at a site in
the mouth or the stomachs or the lungs. A
more basic solution gives us more of the
drug in the neutral form, which is able to
permeate through membranes. Let's take as
an example, nicotine's path from the lungs
to the blood and the brain. Nic-, tobacco
leaves are roughly five percent nicotine
by weight. So the vaporized nicotine for
instance from smoking is a neutral form,
it has the N, now has the CH3. So it's a
tertiary amine. it gets through a total of
three cells and six membranes in going
from the lungs to the blood, and then the
brain. Two membranes in the alveolar
epithelium, and four membranes in the
capillary from the blood to the brain. And
again, we have the neutral form of
nicotine, permeating as smokers know
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within just a few seconds from the lungs
to the brain. A very important process
that takes place roughly 150 billion times
around the world everyday when a smoker
takes a puff. In the brain the nicotine
molecule is a weak base, and so it can
easily gain or lose a proton, again, in
milliseconds. Its pK is, pKa is eight,
that is, at pK eight it is roughly half
protonated and h alf deprotonated. And it
is again the protonated, charged form of
nicotine that interacts with nicotine
receptors. The same kind of equilibrium.
Occurs in the lungs as well, and the
cigarette manufacturers know this. And, so
they put ammonium hydroxide in their
cigarettes to maintain neutral pH, or to
make it basic. The result is that the
proton leaves. The nicotine, and that
nicotine is able to be able to be more in
its permanent form and permeates through
the cell membranes. So that is the path
from the lungs to the blood and the brain
taken by nicotine in just a few seconds.
And it obviously depends very importantly
on having a neutral permeant form of
nicotine, even though the charged form is
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what interacts later on with the
receptors. So if we look at the
concentrations of nicotine in the blood
during and after a cigarette, nicotine
enters the blood and from the end eh. It's
probably even faster than shown on this
slide although, it's difficult to measure
it terribly fast. But, within a minute or
so, Nicotine appears in the blood and in
the brain. And, then it rapidly gets
metabolized, gets broken down. We'll talk
about. enzymes and other processes that
break down drugs in the body in a later
session. Here's another example of neutral
drug permeation. It has to do with
Parkinson's Disease. In Parkinson's
Disease, most of the neurons that make
dopamine degenerate, and so the challenge
is to replace the dopamine in the brain.
Dopamine, however, does not enter the
brain. It's charged. As a result,
therapists physicians use levodopa or
L-dopa, which is zwitterionic. It has no
net charge and easily permeates through
membranes, gets into the gets into the
brain where it is decarboxylated by an
enzyme. Remember that an enzyme is a
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catalytic protein. So this decarboxylase
gives us dopamine which can then, in the
brain, which can then be taken up by
neurons. So this is a pro-drug, if you
like. A molecule that is not itself a
drug, but is a precursor to a drug, and is
made into a drug by the body's own
enzymes. Now , the blood-brain barrier is
a special structure. Made by cells lining
the capillary wall called endothelial
cells. the capillaries, the smallest blood
vessels come in two forms. In the
periphery, outside the brain, the
capillaries have spaces in between the
endothelial cells. Leave this space here
through which a large number of molecules
can diffuse. Proteins, non-polar
molecules, polar molecules such as
glucose. But in the brain, as we'll see,
there are tight junctions. seals between
the endothelial cells and as a result
molecules cannot leave the capillary and
go into the brain unless they're small
non-polar molecules. So only small
non-polar molecules can diffuse out of the
capillary. Here's another view of the
endothelial cells forming the blood brain
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barrier. We have a capillary surrounded by
endothelial cells with the tight
junctions, and here are the red blood
cells in the capillary. It used to be
thought that the glial cells formed the
blood brain barrier. They have feet, these
are glial cells, astrocytes, which extend
end feets or end to feet around the
capillary. It used to be thought that
glial cells are the basis of the
blood-brain barrier, but now we know it's
in the filial cells. The structural basis
of tight junctions is a structure called.
sorry the structural basis of the blood
brain barrier is a set of proteins called
tight junctions. So here are two
epithelial cells, one is here. One is
here. They each have double-layered
membranes. In these double-layered
membranes are proteins that make up these
so-called tight junctions. And, you can
think of them as zippers that zip together
the two cells that make up an epithelium
or an endothelio, endothelium. So, we have
one extracellular solution up here,
perhaps the blood. Another extracellular
solution, down here, perhaps the brain.
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And, the tight junctions occur only in the
brain capillaries and prevent molecules
from diffusing through. Drugs in the body
and in cells are an important topic in
drugs in the brain and in new development
for medicatio n.
There is acid-based equilibrium and
permeability which we discussed
protonation and deprotonation. We've
discussed uptake from the stomach, uptake
from smoke crossing the cell membrane.
There's another topic, short-circuiting of
synaptic vesicles. We'll discuss that
topic later in. in later sessions. And
likewise we'll discuss neurotransmitter
transport inhibitors. In, later sessions.
We've discussed the blood-brain barrier.
And, a bit about its molecular base, basis
clearly the fact that the blood-brain
barrier allows molecules to work in the
periphery but not in the brain is an
opportunity for drug specificity, and many
drugs utilize that opportunity. But it's
also a problem for drug delivery, and how
to get around the blood-brain barrier is
going to be a very interesting problem
over the next few years as we try to
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develop better drugs for the brain. We'll
stop here and go on to botulinum toxin in
another session.
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