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The reward pathway

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					Table of Contents

      Abstract                                  p. 2

      Introduction                              p. 2

      The reward pathway                        p. 4

      Cocaine’s effect on dopamine action       p. 7

      Animal experimentation                    p. 8

      The importance of glutamate               p. 9

      Treatment                                 p. 11

      Conclusion                                p. 11

      Annotated Bibliography                    p. 13


       Addiction to drugs is a chronic, relapsing disease that results from the prolonged

effects of drugs on the brain. Drugs affect the part of the brain known as the reward

pathway, which is responsible for helping us to learn to survive by highlighting important

or significant events by making them feel good so that we are encouraged to repeat the

event. This is a necessary part of learning, but when the event involves a drug, the

reward pathway does not know to shy away. Therefore, it encourages the user to repeat

the drug use because it makes the user feel good. The major neurotransmitter involved in

the reward pathway is a chemical called dopamine, which is responsible for the feelings

of pleasure and the highlighting of the important events. One drug that is particularly

addictive is cocaine, which acts by binding to the dopamine transporter. When taken into

the system, cocaine binds to the transporter which normally clears the dopamine out of

the system after it is fired. Therefore, dopamine cannot be cleared out and builds up in

the synapse. In an attempt to down-regulate this process, the neurons produce less

dopamine, even after the drug is not in the system. Then the brain is unable to feel

pleasure without the drug, so the user takes it again and again, which leads to a vicious

cycle of addiction.


       Addiction has long been considered a social problem that only those individuals

who are weak or unmotivated could ever succumb to. Public perception of addiction is

that humans who are addicted to such drugs as cocaine or alcohol are lazy or bad people,

and that the addict could stop if they only had enough willpower to do so. The same

people who hold such beliefs also think that drug addicts do not deserve treatment, except

by the criminal justice system. Recently, studies on the brains of addicted and non-

addicted individuals show that addiction is a brain disease where the drugs cause physical

changes in the brain circuits that make the addicts behave as they do. The definition of

addiction according to Alan Leshner, director of the National Institute on Drug Abuse

(NIDA), is “a chronic, relapsing illness, that results from the prolonged effects of drugs

on the brain…characterized by compulsive drug seeking and use” (Leshner, 1997).

Therefore, addicts need treatment like any other sick person, not in the form of jail time

or huge fines, but by way of curing the disease through medicine and biotechnology.

Addiction is not just a personal problem, it is a serious public health problem that society

needs to address because addiction usually entails the sharing of needles which spreads

diseases such as AIDS throughout the world.

       One particular addiction that is a problem of increasing proportions in America is

cocaine addiction. The United States is presently in the largest cocaine abuse epidemic in

history, with one to three million cocaine abusers estimated to be in need of treatment.

                            Almost one of two Americans between the ages of 25 and 30

                            has at least tried cocaine (Gawin, 1991). Cocaine comes from

                            the plant called Erythroxylon coca, and is a local anesthetic and

Figure 1. Picture of a      central nervous system stimulant. It is taken by chewing on
coca leaf and powder.
Used with permission        the coca leaves, smoked, inhaled, or injected. In history,
by the National Institute
on Drug Abuse.
                            cocaine has been used in the medical field to relieve or prevent

pain. In 1886, John Pemberton developed the popular soft drink Coca-Cola, which is a

drink that originally contained cocaine and caffeine. The cocaine was removed from the

drink in 1906 (but it kept the caffeine). In 1914 the Harrison Narcotic Act made cocaine

illegal, but this did not stop the drug from spreading across society as an illicit drug

(“Cocaine”, 2000).

         Within seconds or even minutes of taking in cocaine, it causes a feeling of

euphoria, excitement, strength, and reduced hunger. This “high” usually lasts about an

hour, and then the user crashes into a period of depression, which normally causes the

user to take more (“Cocaine”, 2000). This cycle quickly leads to addiction. Cocaine can

cause immediate danger in the form of death from overdose, and it is also highly

addictive and dangerous in the long term. Cocaine is a stimulant and affects the brain’s

reward pathway, which is a set of circuits that are fired in response to pleasurable events.

The chemical signal that transmits the impulse is called dopamine and cocaine works by

blocking the re-uptake of dopamine by the neurons, which makes the dopamine stay in

the gaps longer than normal. All addictions are based on alterations that occur in this

reward pathway, but I will focus on cocaine as a case example throughout the entire


The reward pathway

         Everyone has cravings for something at some point in their life, whether it is a

chocolate bar at midnight or to win more money gambling. These are normal cravings

that all humans are sometimes succumb to. Some humans begin to experiment with

drugs and therefore get cravings for illegal substances such as cocaine or marijuana.

Drug addictions center around alterations in a single pathway in the brain that naturally

rewards us for performing activities that keep us alive (Society for Neuroscience, 1997).

This pathway is known as the “reward circuit” which extends from the forebrain through

the midbrain and into the hindbrain (Barnes, 1988). The circuit includes a set of neurons

                                                        found in the ventral tegmental area

                                                        (VTA), which connect to the

                                                        nucleus accumbens, and to other

                                                        areas such as the prefrontal cortex

                                                        as shown in Figure 2. This

                                                        network of neurons, or nerve cells,

                                                        is activated when we perform

Figure 2. This drawing of the human brain shows the      functions that help us stay alive,
three major areas that are involved in feelings of
pleasure. The prefrontal cortex, the nucleus             such as eating. It provides reward
accumbens, and the VTA make up the “reward
pathway.” Drawn by Amy McGinty.
                                                         and associated pleasurable

feelings, which lead us to repeat the activity and sustain life (Society for Neuroscience,

1997). Other areas within the brain that are associated with the reward system are the

hippocampus which is the brain’s center of learning and memory, the amygdala, which is

the site of our emotional responses to experience, and the hypothalamus, which is the tiny

area in the center of the brain that controls the hormones for sex, thirst and hunger

(Powledge, 1999).

       However, most abused drugs are now known to simulate this pathway and even

alter it a bit so that drug abusers and addicts are dependent upon the drug to survive.

Abused drugs stimulate the same reward system and can induce even greater feelings of

pleasure than the natural functions. This can lead to the drug user bypassing survival

activities in order to only use the drug because the drug makes them feel better than

everyday activities (Society for Neuroscience, 1997). This pathway is also known to

figure in addictions to things other than illicit drugs, such as compulsive eating,

gambling, exercise, and sex. The pathway governs motivated behavior by providing us

with an incentive to learn and repeat adaptive behavior, called reinforcement, which

keeps us alive. Eating is necessary to live, and when we eat something, it most often

provides us with a feeling of pleasure. The reward system is activated when we eat to

make us feel the pleasure so that we will do it again and again.

Dopamine involvement

       The major chemical signal that is involved in the reward pathway is the

neurotransmitter dopamine. Neurotransmitters are the chemicals that are released by the

ends of neurons that cross the synapses (gaps) from one neuron to the next as shown by

Figure 3. They are what carry a signal from our brain to our muscles or vice versa.

  Figure 3. Signals jump from
  neuron to neuron by way of
  chemical messengers (such as
  dopamine) that are stored in
  presynaptic endings, get
  released into the synapse and
  stimulate the next neuron by
  way of the post synaptic ending.
  Drawn by Amy McGinty.

Once the chemical signal is released into the synapse, it attaches to the postsynaptic cell

and fires it and is then immediately either broken down by enzymes, vacuumed up by a

transporter molecule, or stored for reuse by the presynaptic cell that released it. It is

necessary to get rid of the neurotransmitter as soon as the postsynaptic cell is fired in so

that the cells can prepare for the next signal to come through and the same signal isn’t

fired again and again unnecessarily.

       In the reward pathway, dopamine is released into the synapse and then sucked

right back up by transporter molecules. However, addictive drugs interfere with normal

dopamine workings by either releasing excess amounts of dopamine which will intensify

the signal or allowing the dopamine to stay in the synapse much longer than normal

which will lengthen the signal time. The correct amount of dopamine release leads to

such feelings of enjoyment and delight whenever we do something pleasurable. Defined

biochemically, “bliss is what we experience when that bolt of dopamine lightning strikes

in the nucleus accumbens” (Powledge, 1999). However, new research in the area of the

dopamine pathway suggests that the amount of dopamine released into the synapse is not

necessarily directly proportional to the amount of pleasure that is felt. Researchers now

think that dopamine’s chief role is to draw attention to a rewarding or significant event to

encourage us to repeat the event. Linking experience with emotion is the brain’s primary

aid to learning and guiding future behavior, so the neurotransmitter dopamine can be

thought of as a facilitator to learning. Some scientists think that dopamine causes the

frontal neurons (where short-term memories are held) to hold onto some temporary

memories for longer, which increases the chances that they will stick in the mind

(Wickelgren, 1997). This is very important for us humans for survival when this event is

something good such as food, but when the pleasurable event is caused by drug use, the

user will associate good feelings with drug use and continue to use the drug. Continued

use of the drug will cause physical changes to the neurons in the brain and spinal cord,

which leads to addiction.

Cocaine’s effect on dopamine action

       All drugs affect the human body differently, but according to Alan Leshner

“every drug of abuse works through the dopamine system.” Along with dopamine, the

most important player in the reward system when it comes to studying addiction is the

transporter molecule that is supposed to capture the dopamine released into the synapses

and then pump it back into the nerve cell where it gets repackaged in storage vesicles to

be used again (Balter, 1996). Cocaine is able to imitate dopamine so well that it binds to

the transporter instead of the dopamine binding to it, so the cocaine is taken away by the

transporter and the dopamine stays in the synapse (Powledge, 1999). Extra dopamine in

the synapse stimulates more than the usual amount of reward pathway neurons, which

causes an intense amount of pleasure that the brain “remembers” and will want to do

again (Barnes, 1988). Cocaine also blocks the reuptake of serotonin and noradrenaline

into brain cells, which are both additional neurotransmitters that are used in the brain

pathways. At high concentrations, cocaine acts as a local anesthetic because it blocks the

ion channels that allow sodium ions to flow into nerve cells. If sodium ions do not flow

into the nerve cells, the signal cannot be passed along (Barnes, 1988). The evidence that

cocaine stimulates certain structures in the brain reward pathway mostly comes from

experimentation with animals because human experimenting is not possible due to how

dangerous the drug is. However, researchers believe that the human response is very

similar to the animal one.

Animal experimentation

       A research team led by Marc Caron of the Howard Hughes Medical Institute lab

at Duke University experimented with their own genetically engineered mice to see what

role the transporter molecule played in the dopamine/reward pathway. A strain of

“knock-out” mice were created which lacked the gene that makes the transporter protein,

so these mice were not able to take dopamine back into the cells after a signal is fired.

Therefore, in these mice, dopamine stayed in the system for a long time and caused the

mice to become markedly hyperactive. By this experiment, Caron and his colleagues

concluded that the transporter is the key factor in controlling dopamine levels. Then, the

researchers injected cocaine into the system, and the knockout mice were completely

unaffected by the injection which confirms that the drug exerts most of its effect through

the transporter molecule. One surprising finding was that the knockout mice brains were

measured to produce much less dopamine than mice who have the transporter gene,

which shows how the mice brains tried to down-regulate the entire dopamine system.

The neurons released less dopamine even when stimulated, but the amount released

stayed in the synapse 100 times longer than usual which led to enhanced signals despite

the lower concentrations of dopamine (Balter, 1996). This explains why humans and

animals experience a crash after cocaine use; the brain makes less dopamine and there is

no cocaine there to stimulate the pleasure, so less pleasure is experienced, which is the

resulting “crash.”

       One reason cocaine addiction is so bad is because it causes such high amounts of

dopamine to stay in the synapses while the cocaine is present. However, after the cocaine

goes away, the brain tries to get rid of the extra dopamine and in effect gets rid of almost

all of it. This makes for a drop in dopamine levels when a cocaine user is not using it.

The drop in dopamine causes a drop in the amount of pleasure felt, which can cause

depression and the inability to be happy on our own. This also leads to more cocaine use

in order to get back to the happy state and the vicious addiction cycle continues.

The importance of glutamate

       Addiction does not rely solely on the dopamine system. There are other

neurotransmitters systems involved as well, including serotonin, norepinephrine, and

glutamate. Recent research on glutamate suggests that it plays an important role in the

causes of addiction. Glutamate is the neurotransmitter that is most associated with the

learning process and is the main trigger in the complex cascade of chemical reactions that

convert short term memories into long term ones (Powledge, 1999). Intense and

powerful experiences from the use of addictive drugs such as cocaine become embedded

in the user’s memory, and these memories are linked to the people, places, and

paraphernalia associated with them. Thereafter, these associations alone can trigger

cravings for the drug. The user will see something that they remember was associated

with the intense feeling of the drug, and at that point, they will want the drug again

because glutamate made that memory long term. Glutamate is also a major player in the

dopamine system as well, because the dopamine system is regulated by glutamate-

containing neurons. Glutamate is what drives the neural cells to pass along the message

the drug gives (Powledge, 1999). Dopamine and glutamate are the two chemicals found

within the brain that work together to help us pass along pleasure signals and then

remember for later use.

       All addictive drugs affect the reward system the same way; they increase brain

levels of dopamine in one way or another. Stimulants such as cocaine elevate synaptic

levels of dopamine and block the dopamine transporter as mentioned above. Dopamine

and glutamate interact to produce such intense pleasure that one wants to repeat the

experience again. This is how addiction, also known as dependence occurs. Initially, the

drug use is a voluntary behavior, but once the drugs are taken, they change the brain in

such a way that the user cannot live without the drug so they must continue to take it

again and again.

       Dependence can mean either physical dependence or psychological dependence.

Physical dependence is when actual changes in structure and function of the brain take

place and the user literally cannot survive without the drug. Withdrawal sickness occurs

when the user doesn’t take the drug, and this withdrawal process is extremely painful and

can be deadly in some cases. Drugs can be psychologically addictive in the way that they

alter the neurons in the brain, which causes the human to feel depressed and anxious

when the drug is not available (Powledge, 1999). Both kinds of dependence make

addiction a real brain disease, not just a social problem as most people believe.


       The major goal of treatment must be to reverse or compensate for the changes that

are made in the brain by years of drug abuse. This can usually happen through

medications or behavioral treatments (Leshner, 1997). Criminal action will punish the

abuser but will not cure the problem. As a matter of fact, addiction is rarely an acute

illness, it will plague a victim for years after they come clean, because it is generally a

chronic, relapsing disorder. Reasonable treatment for addictions of any kind will focus

on the management of an illness rather than a quick fix cure. Drug treatment for

addictions is a new area of biotechnology, and is focusing on the dopamine pathway as its

target, particularly the transporter molecule, which we discovered earlier is the key to

dopamine re-uptake, and the dopamine receptors on the postsynaptic neuron. One drug

called methylphenidate increases dopamine levels by blocking cocaine’s binding to the

transporter and is in phase I trials (Morris, 1998). Prescription drugs such as this one,

along with professional psychological treatment are both necessary to stop addiction to

drugs such as cocaine.


        Illegal drugs such as cocaine causes changes in the way our brain normally works

to provide feelings of intense pleasure for a short amount of time. However, once that

feeling wears away and the drug is no longer in the body, the pleasurable feelings go

away as well and a depressing crash results from lowered levels of dopamine released

into the neural synapses. This causes the user to use the drug again to get back to the

pleasurable state. Drug use over a period of time causes the neurons to almost

permanently be unable to respond to normal signals which leads to alterations in they

way the user thinks and acts. Addiction is a result of such alterations in the brain reward

pathway and is a serious brain disease, not just a social problem of “bad” people. The

initial use is voluntary and usually social, but the end result of continued use is an actual

disease that must be treated by professionals, not prisons. Addicts who are committed to

jail for their habits will never be treated for the chronic, relapsing disease that results

from the prolonged effects of drugs on the brain and will likely suffer a great deal

throughout their entire life.


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