Lesson 6: The Addicted Brain
The American Psychiatric Association publishes a regularly revised Diagnostics and
Statistics Manual (DSM) for mental disorders. DSM-V (version 5) was published in May
2013. Although addiction is described as a mental disorder in DSM-IV, DSM-V includes
in that definition addiction to activities such as gambling, not just substances.
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Tolerance
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Dependence
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Withdrawal
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Reward-Deficiency Syndrome
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Relapse
Pavlovian learning
Having learned about brain parts and neuron function, you can put it all together in order to understand
how the brain and neuronal networks are involved when a person becomes addicted to a drug.
Understanding the reward pathway is only part of understanding how neurons conspire against us to
create and reinforce drug seeking behaviors. Similarly, dopamine is only one of the neurotransmitters that
influence addiction.
Objectives
After successfully completing this lesson you will be able to:
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describe neuronal substructure in the context of the reward pathway;
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put other neurotransmitters into the addiction story;
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put other brain structures into the addiction story;
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discussion addiction from a perspective of timeline;
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identify the hallmarks of addiction and decide if a new compound is addictive based on these
hallmarks; and
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explain relapse and options for enabling withdrawal and preventing relapse.
Guiding Questions
Consider these questions as you proceed through the lesson:
1. How does dopamine influence addiction?
2. How is glutamate’s influence similar to, and how is it different from, dopamine’s?
3. What is the role for the hippocampus in addiction?
4. What is the role for the amygdala in addiction?
5. What are the stages of addiction?
6. What are the hallmarks of addiction?
7. How does a person break free from addiction?
8. Why do people relapse?
Lesson 6: Activities .
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Before You Begin Lesson 6! (Survey)
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Activity 1: Website Review—The Addicted Brain
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Activity 2: Addiction Stages
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Activity 3: Biochemistry of Addiction
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Activity 4: Addiction’s Hallmarks
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Activity 5: Drug Addiction Treatment
o
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
Career Path: Chemical Dependency Professional
Activity 6: Relapse
Activity 7: Reading—The Addicted Brain
Activity 6-1: Website Review—The Addicted Brain
Start this lesson at:

NIH: Neurotransmission Simulation
https://science.education.nih.gov/supplements/nih2/addiction/activities/lesson2_neuronsseries.html
In some ways, this animation allows you to review your previous lessons, and in other ways it helps you
consider how to build those lessons into a deeper understanding of brain circuitry and dopamine reward.
Try all four cases. These can be frustrating to use because if you get it wrong, you are not told where
your mistake was. The diagram is always the same. Don’t study the amount of activity in the diagram; it
doesn’t change. Start by noting three things. Whether the input is inhibitory or excitatory, what the first
neuron releases (what neurotransmitter), and what the second neuron releases.
Guiding Questions
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What are two ways to decrease dopamine release?
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What are two ways to increase dopamine release?
If one inhibits inhibition, what is the result to a system of linked neurons?
Next, visit:
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NIH: Long-term Effects of Drugs on the Brain
https://science.education.nih.gov/supplements/nih2/addiction/activities/lesson4.html
Be sure to step through the first four (of 13) steps of this video. The first two portions will be review
of the reward pathway from Lesson 3: The Brain. The unassigned steps will be covered in future lessons,
so feel free to peek ahead now if you are inclined.
Guiding Questions

What is the neurotransmitter commonly associated with drugs of abuse?
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What do PET scans show that help us understand the role of amygdala and craving?
What is tolerance? What are two explanations for tolerance (what molecules have changed)?
Last, watch the interviews that are found here:

NIH: Drug Addiction Is a Disease, So What We Do About It? (video interviews)
https://science.education.nih.gov/supplements/nih2/addiction/activities/lesson5_interviews.html
Each row represents many sides to the same person’s story. Please note that there is a lot of content
here; plan accordingly, it might take you 30 minutes to get through all the stories.
When you finish, consider the following questions.

In what ways is addiction like Mike’s diabetes and Carol’s high blood pressure? How is it different?
Activity 6-2: Addiction Stages
A baby is not born with a bottle of beer in her hands. We become addicted. Conversely, an alcoholic
considers herself to always be an alcoholic, even if she is abstinent for years. Addiction is a state of mind,
an involuntary urge to do something, one that is hard to ignore. And addiction happens over time.
Arguably, no one who uses a drug once is instantly an addict (though some would argue that
methamphetamine is just this addictive). And no two people are equally easily addicted to the same drug.
Therefore, addiction can be considered in several stages and the ability to succumb to or avoid the
warning signs of these stages differs from drug to drug and from person to person. What are the stages of
addiction?
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Initiation: initial exposure—do you want to try something that might be dangerous or illegal or at
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least merely self-gratifying?
Continuation: continued use—do you keep using something despite it being “frowned upon” by law
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or friends or family?
Cessation: stopping—can you stop using that thing when you choose to? Or do you continue to use
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it despite severe harm to self or others?
Relapse: after you do succeed in quitting, can you stay “clean”? How difficult is it to fight the urges?
What triggers those urges?
Consider the playing of video games for a moment. You didn’t always play video games (maybe you still
don’t, in which case substitute doing sudoku or crossword puzzles or any other activity you do a lot). You
had to start playing in order to get to the point of being hooked. And playing video games is not
necessarily helping you. You aren’t learning new ideas, you aren’t paying the bills, you aren’t helping your
people when you play video games. But for some people, gaming still draws them in and for others, it is
hard to deny the urge to game. Could you stop playing if you chose to? Have you tried? Have you known
someone who quit and then fell right back into their obsessive gaming behaviors?
Each of these stages involves different brain functions (or dysfunctions). And each of these stages can be
influenced by outside factors differently. Therefore we’ll consider addiction in stages.
Activity 6-3: Biochemistry of Addiction
In a brain that will become or has become addicted to a substance or activity, there are numerous
biochemical changes. Some of these changes apply to neurotransmitters and these changes track nicely
with the stages of addiction you learned about in Activity 6-2. Other changes apply to molecules we have
not yet discussed, ones that relate to neuronal "memory"—alterations in the neuron's chemical profile that
marks it as an oft-used neuron.
First, consider the biochemical changes to neurotransmitters.
View this presentation about what we know about the biochemistry associated with these stages of
addiction:

Presentation: The Biochemistry of
Addiction (https://uweoconnect.extn.washington.edu/public_biochemistryaddiction/. by Dr. Linda
Martin-Morris (8:48)
NOTE: We've narrowly defined a neurotransmitter as a biological signal sent by one neuron to another
electrically excitable cell at close range. We typically think of neurotransmitter receptors as sitting on the
post-synaptic membrane. Interestingly, there are some neurotransmitter receptors that are located on the
pre-synaptic cell. Pre-synaptic glutamate receptors are quite susceptable to long-term drug use and they
help a neuron to adapt to this drug use by moderating the amount of glutamate neurotransmitter that can
be released into the synapse. And, this pre-synaptic glutamate signal is sent by neuroglial cells! For any
"rule" in biology, there are, usually important, exceptions.
Next, visit this site:
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Depression or Substance Abuse, Which Came First?
http://www.addictionsearch.com/treatment_blog/depression-or-substance-abuse-which-camefirst_54.html
Try to answer this question: What is the relationship between depression and addiction?
Then, visit this site (section on Drug Abuse and Addiction):)

NIH: How Science Has Revolutionized the Understanding of Drug Addiction
http://www.drugabuse.gov/scienceofaddiction/addiction.htmll
Guiding Questions
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What kinds of risk factors predispose someone to use drug?
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What aspects of drug use are voluntary?
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What do imaging studies reveal about brain regions that make voluntary decisions in a drug uses?
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What are some risk factors that relate to:
o
How a person uses the drug?
o
When the person uses a drug?
Next consider the biochemical changes that mark neurons as frequently used.
The brain has the ability to modify its functions to adapt to the ever-changing environment that the
organism encounters. Neurons themselves have memory. At the neuronal level these changes may occur
at the synapse, both functionally and structurally. The ability of the synapse to change in this fashion is
called “synaptic plasticity”.
There are small, chemical alterations that occur to mark some neurons or synapses as particularly
important. We know this because the strength of a synapse is not stable, but grows stronger with
use. Santiago Ramón y Cajal, from Spain, first suggested that this type of change might underly learning
and memory without building new neurons. Another phrase associated with strengthening a synapse is
"long term potentiation" (or LTP).
It is now clear that such functional modifications are the result of changes in the structural properties of
the synapse so that more or less synaptic activity (synaptic strength) is produced. In the early 2000s
researchers discovered that drugs of abuse produced glutamate-mediated biochemical and molecular
changes in the VTA-NucAcc reward circuit. These changes represented the neurochemical correlate of
LTP and involved increased numbers of specific glutamate receptors, which resulted in enhanced activity
of that circuit. It is believed that these changes are the basis for some of the behavioral properties of the
addictive process. In addition to impacting neurotransmitter receptor number, LTP may also result from
increasing receptor sensitivity. Repeated use of a synapse also results in changes of proteins that affect
the branchiness of dendrites.
There are many biochemicals involved in these changes to the strength of a neuron. For those of you
curious about the nature of these biochemicals, you can investigate further by looking up LTP.
A great place to get more information is at the Cold Spring Harbor's mini-lecture on LTP by Dr.
Seth Grant found here (http://www.g2conline.org/#Learning & Memory?aid=549.).
In the unit test you'll be asked to name three aspects of synapse function that increases postsynaptic sensitivity in a much-used synapse. Here are some video links to help you understand this:
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Very brief description of pre- and post-synaptic changes in strengthened
synapses: https://www.youtube.com/watch?v=GMehTI6DPYI
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For those with more curiosity and time, watch the faculty lecture
https://www.youtube.com/watch?v=1g8TPZSbSgg
Activity 6-4: Addiction’s Hallmarks
To determine if a drug is addictive, it will help for you to consider each of these hallmarks. A drug that
qualifies on all counts is very likely to be an addictive drug.
1. The drug stimulates the Reward pathway.
Consider a couple of non-addictive drugs. Start with aspirin. Aspirin is an analgesic, a pain relieving drug.
It works on brain molecules, in particular on an enzyme that is necessary to convert one chemical into
another chemical that stimulates pain neurons. Aspirin’s enzyme has nothing to do with dopamine, its
manufacture, its release, its recycling, or its metabolism. Aspirin use might make us feel good in
comparison to how we felt when we had pain. But it does not make us feel euphoric. Next, consider the
medications many people with schizophrenia are asked to take. These medications do have something to
do with dopamine. They act like dopamine antagonists. They bind to dopamine receptors and act in a way
that is opposite to dopamine. People who are prescribed these drugs often prefer to not take their
medications (think about the story in A Beautiful Mind) because taking the medication makes them feel
“flat” and lose the pleasure they typically associated with activities like eating, playing, and sex.
Neither of these drugs is addictive because people do not find it hard to resist the pleasure associated
with drug use.
2. The use of the drug leads to Tolerance.
Many drugs are taken originally at low doses but a person needs to take larger doses in time. A drug can
become less effective over time if a person uses it regularly. There are two main reasons this happens.
Both reasons relate to the body compensating for the change in physiology caused by the drug.
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In one scenario, the body induces the expression of genes that encode the enzyme that metabolizes
the drug. Exposure to nicotine results in the body manufacturing more CYP2A6 in order to metabolize
the drug when we use it next.
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In the other scenario, the body compensates for the excess stimulation experienced while on a drug
by making the receptors to which the drug binds less capable. In the case of LSD, the receptors to
which LSD binds become less responsive: their structure is altered in a way that minimizes the ability
of LSD to bind. In the case of MDMA (Ecstasy), the receptors to which MDMA binds become less
numerous.
3. The use of the drug leads to Dependence, making it hard to withdraw from drug use.
Another way the body compensates for its “understanding” that we are bringing a drug into the body is to
turn off the production of similar molecules. For instance, a person who uses morphine for pain will
respond by producing less of the endogenous morphine known as endorphin. Endorphins, like morphine,
are good at minimizing our sensation of pain. It is costly for the body to produce unneeded molecules, so
if we use morphine, the body finds the manufacture of endorphin molecules to be unnecessary and stops.
That’s all fine and good if a person continues to use the morphine. But when he stops, he finds himself in
a lot of pain because the morphine and the endorphin are no longer available. The term Dependence
refers to the state a person finds himself in wherein the body requires the drug to function “normally.” If
we develop a dependence on a drug, the body will go into withdrawal if we no longer use the drug.
Withdrawal to morphine is painful. Withdrawal to drugs used to treat anxiety make a person develop
severe anxiety when they stop using the drug. Whatever effect the drug has on the body when it is used,
generally the opposite symptoms are experienced when he quits.
Activity 6-5: Drug Addiction Treatment
Drug treatment programs exist to help people rise above their addictions when quitting is a hard-to-realize
goal. These treatments usually include behavioral or cognitive therapy as well as drug therapy. Cognitive
therapy might be better addressed in a psychology course, but drug therapy fits right in with our topic.
Two types of substitutes are used by folks trying to quit using an addictive drug. Nicotine smokers might
substitute a patch or gum form of nicotine for their smoked form because it will help them avoid
withdrawal symptoms but would still lessen their risk of smoking-related illnesses. Heroin addicts might
substitute methadone for heroin. Methadone allows them to minimize their withdrawal symptoms because
methadone binds to the same receptors and, like heroin, is an agonist for these receptors. Not only is
withdrawal therefore easier, but they are avoiding illnesses related to needle-use by taking a pill instead.
Keep in mind that neither of these substitutions counts as avoiding addiction. The replacement
substance is also addictive.
Similarly, several pharmaceuticals are being tried to replace the reward pathway stimulation that is lost
when one quits using a euphoria-inducing drug.
Recently, another type of drug is finding favor in the rehabilitation medicine field. In Unit 6, we’ll
ask you to read about how a hallucinogenic drug is being tested as a treatment for addicts. The story
recently written about this approach was written by a Biology 100 alumnus! Feel free to check that
article out now, but beware, there is some questionable language! http://www.villagevoice.com/2010-1117/news/ibogaine-hallucingen-heroin/
(NOTE: There is an interview with Keegan that we'll recommend for you in Unit 6. Journalism is ONE
career that touches on our topic of Drugs and Drug Addiction).
Activity 6-6a: Relapse
Relapse happens. People who make great progress in breaking free of addiction can, with relatively minor
prompting, get right back in to their old ways.
View this presentation about the science behind drug addiction relapse. Focus on the slides
associated with the "Relapse" topic.

NIH: Addiction Science: From Molecules to Managed Care (www.drugabuse.gov/.../addiction-
science-molecules-to-managed-care.)
(Click the "Next" arrow at the bottom of the webpage to proceed through this presentation.)
Activity 6-6b: Relapse
Next, connect the neurobiology and biochemistry of addiction into the neuroanatomy and
biochemistry of relapse. To do this, view this presentation.

Presentation: Relapse (https://uweoconnect.extn.washington.edu/public_relapse_/.) by Dr. Linda
Martin-Morris (5:15)
Activity 6-7: Reading—The Addicted Brain
Read the following after completing the lesson's activities.
Required
Text
Liska, Drugs and the Human Body

Section on Drug Dependence (Addiction) – 1.4 in 7th edition
Media
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
Presentation: The Biochemistry of Addiction
Presentation: Relapse
Internet

Stages of Addiction
http://www.addictionsearch.com/treatment_blog/stages-of-addiction_22.html (Links to an external
site.)
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Depression and Addiction
http://www.addictionsearch.com/treatment_blog/depression-or-substance-abuse-which-camefirst_54.html (Links to an external site.)

National Institute on Drug Abuse on Addiction
http://www.drugabuse.gov/scienceofaddiction/addiction.html (Links to an external site.)

Neurotransmission Simulation
https://science.education.nih.gov/supplements/nih2/addiction/activities/lesson2_neurons-seriesd.html (Links to an external site.)

Long-term Effects of Drugs on the Brain
https://science.education.nih.gov/supplements/nih2/addiction/activities/lesson4.html (Links to an
external site.)

Drug Addiction: Video Interviews
https://science.education.nih.gov/supplements/nih2/addiction/activities/lesson5_interviews.html (Link
s to an external site.)

From Molecules to Managed Care
http://www.drugabuse.gov/pubs/teaching/teaching6/Teaching8.html (Links to an external site.).
Recommended
Internet

Wikipedia sites on drug tolerance and substance dependence and withdrawal.
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Scientific American: Hallucinogens as Medicine (this will be required reading in Unit 6)
http://www.scientificamerican.com/article.cfm?id=hallucinogens-as-medicine (Links to an external
site.)

National Institute on Drug Abuse and Addiction on Treatment
http://www.drugabuse.gov/scienceofaddiction/treatment.html (Links to an external site.)
Conclusion
In this unit, we've analyzed brain structure, chemistry, and function and how it is impacted by the use of
drugs. These foundational ideas will come back in to play when we go through the drugs one-by-one in
Units 4, 5, and 6. Before we get there, we'll spend a little more time laying other foundations. In Unit 2, we
tackle the issues related to pharmacology.