drugs and brain

8/13/2019 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.

drugs and brain

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