9. addiction i

12 01neurLecture 9; Oct 3, 2013Addiction

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

What is a drug? A drug is a substance that can, in relatively

small concentrations, exert a large eect on physiology. All chemicals affect the body in some way, but

the main difference between drugs and non-drugs is that drugs work with extremely small doses.

Drugs can be naturally-occurring or synthetic. Whether a drug is natural or synthetic has no

bearing on its safety or efficacy.

Psychoactive drugs are drugs that can alter mental state by aecting the function of neurons.


Administration and absorption Drugs are usually administered in one of four ways. Of these, oral

ingestion is the slowest method. In general, the faster routes of administration are more addictive, but also more dangerous due to the risk of overdose.

Oral ingestion Drugs are swallowed and ingested. Some drugs readily pass through the

stomach (e.g., alcohol). Injection

Drugs are dissolved in a liquid and injected into the body. Addicts tend to prefer intravenous (IV) injection (e.g., heroin), because the drug reaches the brain very quickly.

Inhalation Some drugs can be absorbed through the lungs by inhalation. Most often the

drug must be vaporized or smoked (e.g., tobacco, marijuana). Insuation (snorting)

Certain drugs are easily absorbed by the blood vessels lining the inside of the nose. This requires snorting the drug in question (e.g., cocaine).


Levels of involvement Substance use:

The ingestion of psychoactive substances in moderate amounts. Substance use does not significantly interfere with social, educational, or occupational function.

Example: having the occasional drink, cigarette, or cup of coffee

Substance abuse: There is no set amount that defines the border

between substance use and abuse. The focus is not on amount, but rather

consequences. Substance abuse happens when the use of a substance significantly interferes with the users life.

Substance dependence: The state in which the user is physiologically

dependent on a drug, showing tolerance and withdrawal.

Involves drug seeking behavior (stealing money to buy drugs, standing outside in the cold to smoke, etc.,)

Substance use.

Illustration from Barlow & Durand, Abnormal Psychology: An Integrated Approach. Cengage, 2011


What is addiction? Addiction is a state of uncontrolled drug use that persists in

spite of negative consequences associated with taking or procuring that drug. Negative consequences include: health effects, cost, family

disruption, loss of (legal) employment, etc.,

Addiction develops over multiple exposures to addictive drugs. It begins with use, followed by misuse, abuse, and finally dependence. Addiction is not an inevitable consequence of trying a drug, but

repeated drug use does raise the risk of addiction.

Addicts are not weak or foolish. As we will see, addiction is very powerful.


What are the properties of addiction? The definition of addiction remains

controversial.

The distinctions between substance use, abuse, and dependence vary a great deal between cultures.

According to the DSM, patients must

have 1 or more of the following symptoms:1. Recurrent substance use resulting in

failure to fulfill major role obligations.2. Recurrent use in situations when

physically hazardous (e.g., driving).3. Recurrent substance-related legal

problems.4. Continued use despite persistent social

or interpersonal problems.


What is the most addictive drug? Defining the most addictive drug

is a very dicult task. How would you measure this?

The addictiveness of a drug depends on the traits of the user (personality, genetics, etc.,)

In one study, addiction experts were asked two questions: How easy is it to get hooked on

these substances? How easy is it to quit?

Illustration from Barlow & Durand, Abnormal Psychology: An Integrated Approach. Cengage, 2011


Tolerance Repeated exposure to a drug can lead to decreased

sensitivity to that drug. This state is called tolerance.

Individuals who are tolerant to their drug of choice must consume more of it to achieve the same eect. This can be expensive, and it is also dangerous because it can

lead to the user taking toxic levels of a drug in order to feel high.

Interestingly, one drug can produce tolerance to other similar drugs by a process called cross-tolerance. This phenomenon suggests that these drugs have similar

actions in the brain. It also raises the possibility of cross-addiction.

It is possible to become tolerant to some eects of a drug, but not others. Example: tolerance to the intoxicating effects of alcohol

develops faster than tolerance to its motor effects.


Tolerance Interestingly, drug tolerance is linked

to the situation in which the drug is taken.

Taking a drug in the same place each time leads to increased tolerance in that place.

This can be dangerous, because that tolerance might not exist in dierent environments, and the user may be at risk of overdose. This might explain mysterious heroin

overdoses.


Sensitization Repeated exposure to drugs leads to tolerance

for many of the drug eects. However some eects actually increase with frequent drug use. This is called sensitization.

Cocaine psychosis shows sensitization eects in humans a normal dose of cocaine is unlikely to induce psychosis at first, but that dose can produce psychotic symptoms if it is repeated many times. (Cocaine psychosis is a temporary condition that

resembles paranoid schizophrenia and can occur in cocaine abusers.)

Rats and mice show locomotor sensitization to stimulant drugs such as cocaine or amphetamine. Repeated, intermittent exposure to these drugs

causes an increase in their locomotor effects.

1) It is possible to count the number of times a rat rears up in his cage after a shot of amphetamine

2) Repeated daily injections of amphetamine leads to an increase in the number of times the rat rears in his cage while on the drug. This is an example of locomotor sensitization.


Withdrawal eects Repeated use of a drug leads to compensatory adaptations in the

brain in response to that drug. These adaptations serve to maintain homeostasis under conditions of drug use. These compensatory adaptations are also responsible for drug tolerance.

Quitting a drug throws the brain out of balance all of a sudden the compensatory changes are fighting against a drug that is no longer present.

Withdrawal eects are usually the opposite of the drugs original eects.

It was once believed that people became addicted to drugs mostly because they were trying to avoid the unpleasantness of withdrawal. This is a bad explanation. Withdrawal effects dont last long enough to

explain drug relapse after years of abstinence.


Withdrawal eects

100

100

100

100

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1. The brain normally exists in a state of drug-free homeostasis.

2. Taking drugs leads to an imbalance.

3. Compensatory adaptations attempt to restore homeostasis.

4. Withdrawal: Quitting drugs leads to an imbalance in the opposite direction.


Genetics: Twin studies An individuals genes never tell the whole

story. For the complicated psychological conditions we discuss in the course, there is never a single gene that is entirely responsible.

How can researchers study genetic influences on disease if they dont know where in the genome to look?

A good way to start is to use a twin study.


Genetics: Twin studies Identical twins (aka monozygotic twins) have exactly the same genes. They

share 100% of their genes. Fraternal twins (aka dizygotic twins) only share 50% of their genes.

Since twins are born at the same time, and presumably raised the same way, researchers can use them to answer questions about the relative contributions of genes and environment.

A condition is said to be 100% genetic if identical twins always have 100% concordance for that condition. Concordance is when both twins match each other on that condition. Identical twins have 100% concordance on eye color they always have the

same colored eyes as each other because eye color is 100% genetic. Identical twins only have 48% concordance on schizophrenia, because

schizophrenia is only 48% genetic (the rest depends on the environment, bad luck, etc.,)

These studies can be made more elaborate and accurate by also looking at twins that are adopted into separate households. This allows researchers to better estimate the contribution of the environment.


Genetics The genetic links to alcoholism are commonly

studied, because alcohol is legal and widely used. Twin studies suggest that the genetic

contribution to alcoholism is between 50-70%.

There is some overlap between addiction to dierent drugs. For example, twin studies suggest that alcohol

and nicotine (cigarettes) share more than 60% of their genetic vulnerabilities.

Thanks to recently developed molecular biology techniques, we are now learning more about specific genes related to addiction. Some examples: 5HTT: Serotonin reuptake transporter BDNF: Brain-derived neurotrophic factor:


Why start using drugs? Given the risk of addiction, why would anyone want to start

using drugs?

Drugs produce a set of physical and psychological eects collectively referred to as intoxication.

Intoxication is caused by the drugs eects on the CNS. This causes alterations in perception, mood, personality, decision

making, motor control, etc.,

Psychoactive drugs often produce euphoria carrying well (G.) a state of happiness and positive mood.

Drugs, in general, feel good, but why?


What is reward? The term reward refers to stimuli that are in

some way desirable or positive and can aect behavior. Examples: food, money, Pokmon cards,

drugs.

Humans, like other animals, naturally find certain activities to be rewarding. This is with good reason, as rewarding activities are usually critical to survival. Examples: eating, sleeping, sex, exercise,

etc.,

Rewarding stimuli can be dierent depending on an individuals personal experience. Therefore, we learn to value more than just what were born liking. The ability to learn new rewards is also

valuable, because it teaches us to repeat successful behaviors.


The reward system The essentials of life often have homeostatic and hedonic

components. Homeostatic: the fulfillment of physiological needs (nutrients, etc.,) Hedonic: the pleasurable or rewarding feeling that is often

correlated with homeostatic fulfillment.

There is a system in the brain responsible for making these behaviors more rewarding.

The various addictive drugs are able to, through a number of chemical mechanisms, hijack and take over the functioning of this system. This causes large amounts of pleasure with no real substance.


Discovery of the reward system Olds and Milner (1954) discovered the

phenomenon of intracranial self-stimulation (ICSS) more or less by accident.

In the first ICSS experiment, a rat was fitted with an electrode located in a certain part of his brain.

This electrode was connected to a stimulator that was controlled by a lever in the rats cage.

The rat could therefore self-stimulate that part of his brain.

Setup of the ICSS experiment, using a modified Skinner Box

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


Discovery of the reward system Depending on where the electrode was

placed, the rat would press the lever a huge number of times almost endlessly.

Rats would press the lever thousands of times an hour, ignoring everything else that the experimenters could oer. Rats would ignore food, water, access to a

sexually receptive female, and whatever other rat treats the experimenters could think of.

The rats would eventually collapse from exhaustion or else be forcibly removed from the experimental cage.

To researchers, this sort of behavior closely resembled the behavior of human drug addicts. They reasoned that the brain areas targeted by

the electrodes must therefore be involved in drug addiction.


Discovery of the reward system The discovery of ICSS ushered in a new era in the study

of addiction, because it revealed a circuit in the brain that is responsible for rewarding behaviors and the accompanying sensations of pleasure.

The ocial name for this circuit is the mesocorticolimbic dopamine system, but sometimes it is called the reward system for short.

The anatomy of this system is hinted at by its name. It begins with a structure in the midbrain called the ventral tegmental area (VTA). Neurons in the VTA project axons to regions in the limbic system and cortex.

Dopamine is the main neurotransmitter used in this system.


The mesocorticolimbic dopamine system Ventral tegmental area

(VTA) Contains neurons that

produce dopamine. Axons from these neurons project to the:

Hippocampus (Hipp) Nucleus Accumbens

(NAc)

Prefrontal Cortex (PFC)

Midbrain

Limbic

Cortical

PFC! NAc! Hipp!

VTA!


The mesocorticolimbic dopamine system When a rewarding stimulus is

detected, neurons in the VTA are activated. They release dopamine into the PFC, NAc, and Hippocampus.


The mesocorticolimbic dopamine system Every addictive drug aects this system

in some way. Addictive drugs increase dopamine

release in the Nucleus Accumbens (NAc).

The purpose of dopamine release in the NAc seems to be a teaching signal. This is related to the expectation and

experience of a rewarding stimulus. Unexpected rewards lead to especially

large dopamine release.

Together with the PFC and Hippocampus, this system allows for the experience of reward, as well as the learning needed to go after it again. In this case of natural, healthy rewarding

stimuli, this system is quite useful.

The mesocorticolimbic dopamine system.


The mesocorticolimbic dopamine system

In general, addictive drugs lead to supraphysiological dopamine. In other words, a dopamine release that is much larger than what would normally be seen with naturally occurring rewards.


The mesocorticolimbic dopamine system on drugs By over-stimulating the

mesocorticolimbic dopamine system, addictive drugs hijack our brains reward system.

Because of this, the brain begins to over-prioritize behaviors and stimuli it has associated with drugs.

In this way, the life of the drug addict quickly spins out of control, as the normal, healthy behaviors regulated by the reward system fall by the wayside.


The mesocorticolimbic dopamine system on drugs By over-stimulating the

mesocorticolimbic dopamine system, addictive drugs hijack our brains reward system.

Because of this, the brain begins to over-prioritize behaviors and stimuli it has associated with drugs.

In this way, the life of the drug addict quickly spins out of control, as the normal, healthy behaviors regulated by the reward system fall by the wayside.

But.Each drug also acts on various other neurotransmitter systems to produce the unique effects of that drug.!


How to study addiction? Addiction can be studied in the lab

using a variety of methods. One of the most popular and useful of these is called self-administration.

In the self-administration model, a rat is implanted with an intravenous cannula connected to a machine that automatically dispenses small injections of a drug.

The rat is placed in an operant conditioning chamber, much like the one used for ICSS, and it is able to press a lever to receive a small shot of the drug.

A rat in a self-administration apparatus


Self-administration By employing the principles of operant

conditioning, it is possible to use the self-administration setup to estimate how addictive a drug is.

In a progressive ratio schedule of reinforcement, every time the rat gets an injection of the drug, the next injection costs more lever presses. E.g. the first injection requires 1 press, the

next 2, then 4, 6, 9, and growing exponentially as high as 901.

At a certain point, the rat will give up pressing the lever. But how long it holds out before giving up is used as an index of how hard it is willing to work for the drug. This is called the breakpoint.

A rat in a self-administration apparatus

9. addiction i

Documents

addictive drugs

psychoactive drugs

injection drugs

drugs work

absorption drugs

certain drugs

repeated drug use

substance dependence