10. Addiction II

12 01neurLecture 10 ; Oct 8, 2013Addiction

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

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


The assignment! Keep in mind that we are marking assignments on content

and effort (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.


Assignment rubric


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!


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.


How to submit a Facebook group on a Mac (example)

1)%Browse%to%the%event/group%

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%

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


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!


Some example Tweets

Source:%Gaser%C%&%Schlaug%G.%Brain%Structures%Differ%between%Musicians%and%NonMMusicians.%%

The$Journal$of$Neuroscience,%2003.%

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


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


Example definitions Definitions are marked out of 2, and should include two pieces of information on the

definiendum (the word being defined).

Example:

-Drugs are bad4) Drug

-Substances that affect the function of the brain and body

4) Drug

-Substances that exert a relatively large effect on physiology.-Can be naturally occurring or synthetic

4) Drug

0 - bad

1 - ok

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 explain why addiction is a long-lasting disorder

2 - good

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 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.

4 - best


How to get help1. Contact your TA, ask questions via email or arrange an

appointment.

2. Contact me, or visit my office hours: Wednesday 3:30-4:30 Room 305 Life Sciences Research Building

3. Pre-exam online office 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%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 caffeine 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 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.

Cocaine was once a key ingredient in Coca-Cola (the name is not a coincidence.)

Cocaine is also a powerful local anesthetic, so it made an excellent cure for toothaches.


Acute effects 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 effects of cocaine resemble what happens when the sympathetic nervous system (SNS) is activated.

Physiological effects: Increased locomotor activity, tachycardia (racing heart), increased

blood pressure, increased body temperature, pupil dilation, increased blood glucose.

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


Acute effects 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 effects, combined with how quickly the effects 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.


How does cocaine affect the brain? Cocaine is highly addictive. Based on what weve learned

about the mesocorticolimbic dopamine system, it is reasonable to expect that cocaine somehow affects this system.

The question is: how?


PFC! NAc!Hipp!

VTA!


Focus on synapses in the Nucleus Accumbens!


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

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.

Dopamine reuptake !transporter!

Dopamine receptor!


Cocaine at the synapseWhen 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 effects of cocaine.

Dopamine reuptake !transporter!

Cocaine!


Tolerance to cocaineDopamine reuptake !transporter!

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.

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 effect of reducing the users enjoyment of cocaine, causing them to take more and more of it.

Dopamine receptor!


Cocaine withdrawalDopamine reuptake !transporter!

Dopamine receptor!

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.


Cocaine withdrawalDopamine reuptake !transporter!

Dopamine receptor!

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.

NoteCocaines ability to block the dopamine reuptake transporter comes from the fact that the cocaine molecule is chemically similar to the dopamine molecule. In essence, it can fit into the transporter just enough to get stuck.Virtually all drugs have a resemblance to a naturally occurring chemical in the body. Some drugs stimulate receptors directly, others affect neurotransmitter levels by interfering with neurotransmitter release, reuptake, and enzymatic degradation.


Antagonists and agonists Drugs that affect 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 affect 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?


Drugs against drugs Developing an effective strategy against

drug addiction is a major priority for researchers today.

The acute effects 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.


Drugs against drugs The effects of alcohol cannot be so easily

shrugged off, but Disulfiram (Antabuse) allows a slightly different 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.


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 effects 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.


A vaccine for cocaine?

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.

1.2.

3.


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 anti-cocaine antibodies, cocaine cannot reach the brain. Without that rush, cocaine

seems to be much less addictive.

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.


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.

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


Mouse party!

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

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10. Addiction II

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