Lecture 10 ; Oct 8, 2013

n e u r1
2 0
1

Addiction

The assignment!
Now that youve all* submitted your proposals, heres what to
expect:
Since the proposal is pass/fail, you may get either a 0 or a 5.
If you get a 5, start working on your project, taking into account
the suggestions made by your TA.

If youre proposed something good, but overly large and ambitious,

we will give you a 5, but suggest breaking the project down and
only doing part of it.

If you get a 0, dont worry, you will have one week from when
your proposal is returned to resubmit.

If you follow the suggestions from your TA and resubmit on time,

you will get a 5 on the proposal.
If you get a 0 and dont resubmit, you should still do the
assignment, but keep in mind that youve already forfeited of its
overall value (and without an approved proposal, you may end up
with a low-quality assignment).
*93.29% of the class submitted a proposal

NEUR%1201%%Fall%2013%%Harry%MacKay%

The assignment!
Keep in mind that we are marking assignments on content
and eort (among other things). Check the rubric on
cuLearn for details.
Getting a 5 on your proposal does not guarantee a good
mark on the assignment.
A 5 on the proposal simply means that youve proposed an
acceptable idea. Its still up to you to make into a good quality
assignment.
We will be looking at your effort level and content and grading you
based on that.

NEUR%1201%%Fall%2013%%Harry%MacKay%

Assignment rubric

NEUR%1201%%Fall%2013%%Harry%MacKay%

How to submit
You dont need to worry about this for a while (the assignment is due the
last day of class). But just so you know
You might decide to actually make a Facebook page, Twitter account,
etc., This is fine, but not required.
As Ive said, you can hand in a word document with the content (pictures and
writing) and skip the step of making an account.

If you make a Facebook page, Twitter account, or whatever, please make

your account private.
This guards against plagiarism of your work.

If youve made an online account, please do not just submit a link! We

need a static, final document thats not live online.
This is so we can prove that what you handed in on the due date really is the
final version live online things can be updated after the due date.
This also allows you to include references!

NEUR%1201%%Fall%2013%%Harry%MacKay%

References
Dont forget to include references for things you say in the
assignment.
This includes articles and lectures from this class.

You should include a list of references either separately or

appended to your assignment.
For Tweets, Facebook posts, etc., that use references, cite them
after the post itself in the Word document you submit.

See the Guidelines for Assignment document on

cuLearn for details.

NEUR%1201%%Fall%2013%%Harry%MacKay%

How to submit a Facebook group on

a Mac (example)

1)%Browse%to%the%event/group%
NEUR%1201%%Fall%2013%%Harry%MacKay%

2)%Click%File,%Print%
3)%Click%PDF%and%select%Save%as%PDF%
4)%DoubleMcheck%that%it%worked,%then%
submit%that%PDF.%

How to submit a Facebook group in

Windows (example)

1)%Browse%to%the%event/group%
NEUR%1201%%Fall%2013%%Harry%MacKay%

2)%Click%File,%Print%
3)%Select%Microso./XPS/Document/
Writer%as%your%printer%
4)%Click%OK%and%send%the%resulPng%le.%

Note:
The previous examples work equally well for other sites like
Twitter, Pintrest, etc.,
Just make sure you check that the file contains everything
you want it to before you send it!

NEUR%1201%%Fall%2013%%Harry%MacKay%

Some example Tweets

Source:%Some%guy%from%my%high%school%who%
really%liked%smoking.%%

NEUR%1201%%Fall%2013%%Harry%MacKay%

Source:%Gaser%C%&%Schlaug%G.%Brain%Structures%
Dier%between%Musicians%and%NonMMusicians.%%
The$Journal$of$Neuroscience,%2003.%

The midterm!
October 17th, here, during class
time.
Material covered: Lectures 1-12,
articles 1-6.
Types of questions:
Multiple choice (scantron)
Definitions
Short-answer

NEUR%1201%%Fall%2013%%Harry%MacKay%

Example definitions

Definitions are marked out of 2, and should include two pieces of information on the
definiendum (the word being defined).

Example:

4) Drug

0 - bad

-Drugs are bad

4) Drug
-Substances that affect the
function of the brain and body

1 - ok

4) Drug
-Substances that exert a relatively
large effect on physiology.
-Can be naturally occurring or
synthetic
NEUR%1201%%Fall%2013%%Harry%MacKay%

2 - best

Example short answers

Short answers are worth varying amounts (between 1-7 points). At minimum, your answer
should include as many pieces of information as there are points in the question.

Example: Using information from Nestlers article and lectures, explain what the science of
epigenetics tells us about drug addiction? (4)

-Drugs are bad

0 - bad

Chronic exposure to addictive drugs such as cocaine leads to

changes in histone acetylation and methylation. These changes
last a long time after the drug is out of the system, and may 2
explain why addiction is a long-lasting disorder
Exposure to cocaine activates nearly 100 genes in the brain. Chronic
exposure to cocaine leads to increases in histone acetylation and
decreases in histone methylation of genes in reward areas of the 4
brain. This has the net effect of loosening chromatin structure,
leading to long-term increases in gene expression that may explain
why addiction lasts so long. This happens because cocaine affects
the activity of enzymes nicknamed writers and erasers.
NEUR%1201%%Fall%2013%%Harry%MacKay%

- good

- best

How to get help

1. Contact your TA, ask questions via email or arrange an
appointment.
2. Contact me, or visit my oce hours: Wednesday 3:30-4:30
Room 305 Life Sciences Research Building
3. Pre-exam online oce hours: October 16th, 7-9pm

Use Big Blue Button on this classs cuLearn page (available

during specified hours
I will be online the whole time, as will your TAs

NEUR%1201%%Fall%2013%%Harry%MacKay%

NEUR%1201%%Fall%2013%%Harry%MacKay%

Cocaine!

Why study cocaine?

Cocaine is classified as a stimulant, which is
a drug that produces a general increase in
neural and behavioral activity (amphetamine
and caeine are also stimulants).
Cocaine is prepared from the leaves of the
coca bush (Erythroxylon coca).
Cocaine can be further processed with baking
soda to yield crack, which can be smoked.

Cocaine is highly addictive, and is a

commonly abused street drug.

Cocaine was once a key ingredient in CocaCola (the name is not a coincidence.)

Cocaine can be converted to a smokeable

form called crack cocaine.
Cocaines biological activity is fairly well
understood, and so researchers often use it
as a model of addiction in general.
NEUR%1201%%Fall%2013%%Harry%MacKay%

Cocaine is also a powerful local anesthetic,

so it made an excellent cure for toothaches.

NEUR%1201%%Fall%2013%%Harry%MacKay%

Acute eects of cocaine

As a stimulant cocaine generally stimulates nervous system
activity (as opposed to depressants like alcohol, which slow down
the nervous system.)
Many of the physiological and psychological eects of cocaine
resemble what happens when the sympathetic nervous system
(SNS) is activated.
Physiological eects:
Increased locomotor activity, tachycardia (racing heart), increased
blood pressure, increased body temperature, pupil dilation, increased
blood glucose.

Psychological eects:
Euphoria, racing thoughts, reduced appetite, psychosis at high doses.

NEUR%1201%%Fall%2013%%Harry%MacKay%

Acute eects of cocaine

Cocaine reaches the brain very quickly, producing a sudden
rush of excitement and euphoria.
IV injection: ~30 seconds
Smoked (as crack): ~30 seconds
Snorted: 10-15 minutes

Once in the body, cocaine is metabolized and deactivated by the

body very quickly.
Within an hour of taking the drug, blood levels fall to about half of their
peak. After 2+ hours, the drug has almost entirely left the system.

The rapid onset of eects, combined with how quickly the eects
disappear makes cocaine very addictive.
Users are lured by the rush, but since its effects are so short-lived,
they tend to use the drug over and over again.

NEUR%1201%%Fall%2013%%Harry%MacKay%

How does cocaine aect the brain?

Cocaine is highly addictive. Based on what weve learned
about the mesocorticolimbic dopamine system, it is
reasonable to expect that cocaine somehow aects this
system.

The question is: how?

NEUR%1201%%Fall%2013%%Harry%MacKay%

Focus on synapses in the

Nucleus Accumbens!
PFC!

NEUR%1201%%Fall%2013%%Harry%MacKay%

VTA!
NAc!

Hipp!

Cocaine at the synapse

Dopamine is produced by neurons
in the VTA, and is released at
synapses in the NAc, PFC, and
Hippocampus.

Dopamine
reuptake !
transporter!

Recall that neurotransmitters

(dopamine is a neurotransmitter)
should not be left in the synaptic cleft
any longer than necessary. They
must be cleared away by specialized
reuptake transporters.

Under ordinary conditions,

dopamine in the mesocorticolimbic
dopamine system is recycled by
dopamine reuptake transporters
located on the presynaptic terminal.
NEUR%1201%%Fall%2013%%Harry%MacKay%

Dopamine receptor!

Cocaine at the synapse

When cocaine enters the brain, it
blocks the dopamine reuptake
transporter.

When the dopamine reuptake
transporter is clogged by cocaine,
dopamine cannot be recycled back
into the presynaptic terminal.

Dopamine thus accumulates in the
synapse, over-stimulating the
mesocorticolimbic dopamine
system.

This leads to the euphoric and
addictive eects of cocaine.
NEUR%1201%%Fall%2013%%Harry%MacKay%

Dopamine
reuptake !
transporter!
Cocaine!

Tolerance to cocaine
Repeated cocaine administration can lead to
two major compensatory adaptations in the
dopamine synapse. The purpose of these
changes is to compensate for the excess
dopamine caused by cocaine.

Dopamine
reuptake !
transporter!

1. Certain types of dopamine receptors are

removed from the post-synaptic membrane.

2. Dopamine release from the pre-synaptic

terminal is reduced.
These changes may have the eect of reducing
the users enjoyment of cocaine, causing them
to take more and more of it.




NEUR%1201%%Fall%2013%%Harry%MacKay%

Dopamine receptor!

Cocaine withdrawal
The compensatory changes seen in cocaine
tolerance remain in place for a while, even after
the user quits using cocaine. The brain does
not immediately return to normal.



After quitting cocaine, the reduced numbers of
dopamine receptors, and the reduction in
dopamine release can remain for weeks.

Since the function of the reward system is
reduced, nothing will seem enjoyable. This
inability to experience pleasure is called
anhedonia - without pleasure (G.)

The system gradually returns to homeostasis,
but because the transition out of active drug
use involves a period of withdrawal symptoms,
addicts are often unable to quit cold turkey.


NEUR%1201%%Fall%2013%%Harry%MacKay%

Dopamine
reuptake !
transporter!

Dopamine receptor!

Cocaine withdrawal
Note

The compensatory changes seen in cocaine

Dopamine
tolerance remain in place for a while, even after
Cocaines
ability
to does
block the dopamine reuptake reuptake !
the
user
quits
using
cocaine.
The
brain

transporter!
not immediately
return
to
normal.
transporter comes from the fact that the cocaine


molecule is chemically similar to the dopamine

After quitting cocaine, the reduced numbers of
molecule.
dopamine
receptors, andIn
theessence,
reduction in it can fit into the transporter
dopamine
release
can remain
weeks.
just
enough
toforget
stuck.


Since the function of the reward system is
Virtually
all drugs
reduced,
nothing will seem
enjoyable.have
This a resemblance to a naturally
inability occurring
to experience pleasure
is called in the body.
chemical
anhedonia - without pleasure (G.)


Some
drugs
The system
gradually
returns stimulate
to homeostasis,receptors directly, others
Dopamine receptor!
but because the transition out of active drug
aect neurotransmitter levels by interfering with
use involves a period of withdrawal symptoms,
reuptake, and enzymatic
addicts neurotransmitter
are often unable to quit coldrelease,
turkey.

degradation.

NEUR%1201%%Fall%2013%%Harry%MacKay%

Antagonists and agonists

Drugs that aect neurotransmitter function can be broadly
categorized into two groups:

Agonists:

Drugs that ultimately enhance the function of particular neurotransmitter

systems.

May be accomplished by mimicking that neurotransmitter and binding to its receptor.

May also be accomplished by blocking reuptake/degradation

Antagonists

Drugs that ultimately decrease the function of a particular neurotransmitter

system.
May block that neurotransmitters receptor.
May limit release of that neurotransmitter.

Since this is a course on the brain, every drug we talk about will aect
one or more neurotransmitter systems.
Therefore, you should always ask yourself what neurotransmitter system
does this drug affect, and does the drug act like an agonist or an
antagonist?

NEUR%1201%%Fall%2013%%Harry%MacKay%

Drugs against drugs

Developing an eective strategy against
drug addiction is a major priority for
researchers today.
The acute eects of opioid drugs
(morphine, heroin, opium etc.,) can be
blocked by giving the competitive
antagonist naloxone.
Naloxone not only blocks the receptors for
these drugs, it also helps kick bound
drugs off receptors, thus eliminating the
high entirely (this is also useful in avoiding
fatal overdoses).
Naloxone can also be taken pre-emptively,
so users are less tempted to abuse opioid
drugs.
NEUR%1201%%Fall%2013%%Harry%MacKay%

Drugs against drugs

The eects of alcohol cannot be so easily
shrugged o, but Disulfiram (Antabuse)
allows a slightly dierent strategy.
Antabuse blocks the enzyme acetaldehyde
dehydrogenase, which is responsible for
clearing the body of alcohols noxious
metabolic acetaldehyde.
Drinking alcohol while on Antabuse results in
a very unpleasant reaction (something like an
acute super-hangover).

In essence, both of these strategies take

advantage of the fact that willpower
fluctuates throughout the day.
One can take naloxone or antabuse in the
morning, and theoretically not be tempted to
use drugs later in the day.
NEUR%1201%%Fall%2013%%Harry%MacKay%

Drugs against drugs

Drugs to counter cocaine addiction are elusive.
But several strategies are under investigation.
Modafinil a mild stimulant drug that, among
other things, increases glutamate and
dopamine levels, is showing promise as an
adjunct to other forms of therapy for addiction.
Presumably its stimulant action helps reduce
cravings for cocaine.
A 2005 study found it to be helpful in maintain
abstinence, but a 2007 study found only minor
effects.

On the other hand, drugs such as Topiramate

and Vigabatrin act to enhance the eects of the
inhibitory neurotransmitter GABA.
This makes sense, because increasing the
inhibitory potency of GABA can effectively
counter-act the stimulant effects of cocaine.
Preliminary trials with Topiramate and Vigabatrin
show a promising effect on abstinence.

NEUR%1201%%Fall%2013%%Harry%MacKay%

A vaccine for cocaine?

2.

1.

3.
1. Cocaine is chemically linked to the cholera toxin.
2. When injected, the bodys B cells recognize it as a bacterial intruder and
generate anti-cocaine antibodies.
3. Later on, when the user takes cocaine, the bodys acquired immunity kicks in,
and the anti-cocaine antibodies bind to the cocaine molecules.
NEUR%1201%%Fall%2013%%Harry%MacKay%

A vaccine for cocaine?

1. Normally, cocaine quickly
reaches the brain producing
an addictive rush that
keeps people coming back
for more.
2. In a vaccinated user,
however, because cocaine
is bound to the bodys anticocaine antibodies,
cocaine cannot reach the
brain.
Without that rush, cocaine
seems to be much less
addictive.
NEUR%1201%%Fall%2013%%Harry%MacKay%

1.

2.

A vaccine for cocaine?

Vaccines could theoretically be generated for
any drug.
Presently there are clinical trials underway
testing vaccines against cocaine and nicotine.

Like any other treatment for addiction the

success of vaccine treatments depends on the
willingness of participants to quit.
The cocaine vaccine may be especially useful
for this. Immunized users will be protected for
many years, and this can lower the chances of
relapse.
Anti-addiction drug therapy is important, but
the development of such drugs is moving
slowly.
NEUR%1201%%Fall%2013%%Harry%MacKay%

Why doesnt everyone get addicted?

The chemistry of the previous section might make it
seem that cocaine (and other drugs) inevitably lead to
addiction. But this isnt strictly true the risk of
developing an addiction varies between people.

Some people are at high risk for becoming addicted to one

or more drugs, others are at low risk.

Genetics play a role, but nobody has discovered an

addiction gene.

Early life history also seems to play a role exposure to
trauma (abuse, neglect, etc.,) early in life is one of the best
predictors of adult addiction.
This is tied up in a web of socioeconomic factors that
contribute to the drug problem.

The issue is quite complex, but a complete explanation of

drug addiction requires attention to genetic and early-life
factors, as well as an appreciation of the social and
economic issues that lead to drug abuse.

NEUR%1201%%Fall%2013%%Harry%MacKay%

Illustration from J.P.J. Pinel, Biopsychology. Allyn & Bacon, 2011

Mouse party!

http://learn.genetics.utah.edu/content/addiction/drugs/mouse.html

NEUR%1201%%Fall%2013%%Harry%MacKay%