Download MCDB 1041 The Brain and Addiction The Brain`s Reward Pathway

MCDB 1041 The Brain and Addiction
The Brain’s Reward Pathway
The neurotransmitter dopamine is key to “feeling good”. All
neurotransmitters either trigger activity or inhibit activity by binding to
neurotransmitter receptors on another set of cells (called the postsynaptic cells). The release of dopamine from neurons in the Ventral
tegmental area (VTA) is triggered when we eat, have sex, see a beautiful
sunset, watch a football game, etc. Because of the way dopamine acts, it is said to be the main neurotransmitter
in the “reward pathway” of the brain, a system that involves a feedback loop between several different areas:
the VTA, the nucleus accumbens, and the prefrontal cortex. Ultimately, the prefrontal cortex and its connection
to the amygdala determine how we feel (behavior and emotion).
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All drugs of abuse, no matter how different their immediate effects on the body, ultimately upregulate
dopamine reception in the nucleus accumbens. This makes people feel good and makes them want to keep
using the drug. Drug use produces STABLE (persistent) changes at the level of gene transcription in
the brain that are correlated with addictive behavior.
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Dependence: without the extra dopamine delivery, one does not feel good, because the reception of
dopamine is very low.
• Normal activities now trigger less dopamine release than usual
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Tolerance: the same amount of dopamine released from the VTA is now not as pleasurable as it once was.
• Persistent high dopamine DECREASES the number of dopamine receptors; now dopamine is not
present at a high enough level to bind the infrequent receptors.
Repeated drug use can change levels of another neurotransmitter, glutamate. This change seems to be involved
in strengthening the neuronal pathways that link memories of drug-taking experiences with high reward,
thereby feeding the desire to seek the drug.
The drawing below shows how different neurons from different regions of the brain interact to affect the
dopamine receptors in the nucleus accumbens. On the next page, you’ll read about different drugs and
you can draw onto this diagram their mechanisms of action.
Part I. Using the drawing on the previous page to guide you, read about how the drugs below affect the
brain. At each table, focus on one of the drugs (your LA will tell you which one). Read the short passage
below, and summarize on your handout drawing how that drug works (its mechanism of action) and why
it can be addictive (you are welcome to look up more online). Present a summary of how the drug works
to another table, and indicate the sites of action for each drug on your drawing. At each table, make a
comparative chart as a group that illustrates how these drugs/behaviors are different and/or similar in
their in their mechanism of action and their impact on the brain. (you will turn this in at the end of class)
Nicotine
Nicotine is an alkaloid found in the nightshade family of plants that includes tobacco. Nicotine binds to the
nicotinic acetylcholine receptor, bound naturally by the neurotransmitter acetylcholine. These acetylcholine
receptors are present in muscles, and throughout the brain. The nicotine receptor is a complex of 5 proteins,
each encoded by a different gene. There are several variants (alleles) of each of these 5 genes that encode the
nicotine receptor. In the brain, when the receptors are bound, they stimulate the release of dopamine from VTA
neurons, which is then received by receptors in the nucleus accumbens. Thus, the presence of nicotine initially
leads to higher levels of dopamine in this area. In addition, the smoke from a cigarette also includes
monoamine oxidase inhibitors. Monoamine oxidase is an enzyme that breaks down dopamine (and other
neurotransmitters). Ultimately, though, this elevated level of dopamine release leads to tolerance, where less
dopamine is released in the absence of nicotine.
Cocaine
Cocaine does not bind directly to a neurotransmitter receptor, as do some other drugs. Instead, it binds to and
blocks the “reuptake pump” for dopamine, which normally acts to remove dopamine from the synaptic area
(dopamine is taken back into the neuron that released it, and broken down). So, when cocaine is present,
dopamine continues to be released but isn’t broken down, thus leading to an excess of dopamine in the synaptic
area. This stimulates feelings of intense pleasure. Over repeated use, the system becomes altered: less
dopamine is produced in the absence of cocaine than would be produced under normal circumstances, and more
dopamine is required to produce a normal level of pleasurable feelings.
Alcohol
One of the most powerful effects of alcohol is to reduce the pace of brain activity in part by decreasing the
excitatory actions of the neurotransmitter glutamate at the NMDA subtype of the glutamate receptor and
boosting the action of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA)
at the GABA receptor. These actions are among the reasons that alcohol is often thought of
as a depressant. Both of these receptors are linked to channels that function by letting specific ions enter the
cell, and thus affect neuron’s electrical activity. Alcohol administration causes release of dopamine the nucleus
accumbens. Alcohol consumption also affects the activity of opioid peptides, which in turn appears to increase
the rewarding effects of alcohol. In fact, the medication naloxone, which inhibits the function of opioid
receptors, blocks the release of dopamine in the nucleus accumbens and has been shown to suppress alcohol
consumption by laboratory animals.
Heroin
When a person injects heroin, the drug travels quickly to the brain through the bloodstream. Heroin can reach
the brain just as quickly if it is smoked. Once in the brain, heroin is converted to morphine. Morphine binds to
opiate receptors that are concentrated in areas within the reward pathway (including the VTA, nucleus
accumbens, and cortex). Morphine also binds to areas involved in the pain pathway (including the thalamus,
brainstem, and spinal cord). Opiates bind to opiate receptors on dopamine releasing cells, thus triggering these
cells to send a signal to release more dopamine. In fact, the theory is that opiate receptor activation decreases
GABA release, which normally inhibits dopamine release, so dopamine release is increased!
Behaviors that can be addictive like drugs. Example: “Thrill-seeking” behavior:
The three neurotransmitters implicated in thrill seeking are dopamine, which is associated with intensely
pleasurable experiences, serotonin, linked to mood, and norepinephrine, a key player in the “fight or flight”
response. The levels of all three in the brain are regulated by an enzyme called monoamine oxidase (MAO).
MAO breaks down and inactivates all three of these neurotransmitters. How can a behavior be addictive?
When a person engages in the behavior, these neurotransmitters are released. If one is predisposed (by genetics)
to have this behavior, repeating the behavior can lead to addiction (just like repeated use of a drug). The
hypothesis for why individuals can get addicted to thrilling behaviors is that their levels of MAO may be lower
than the normal population. Thus, they seek a higher thrill level to produce a normal amount of dopamine.
Once those behaviors are begun, they could lead the brain into the same kind of addictive responses as a drug.
Individual with lower numbers of D2 and D4 receptors may seek out more dopamine-producing behaviors to
stimulate these receptors—to get the right level of “feedback” (normal pleasurable activities do not trigger
enough dopamine binding). There is also evidence for thrill seekers having a specific allele of the D2 receptor
that may be less receptive than normal dopamine receptors.
Part II.
Read the following studies and discuss it with your small group. Answer the questions below and be
ready to explain the study and your conclusions, as well as any additional information you gather (you
may choose to split your table in half, each focusing on one of the studies). Your goal is both to find flaws
in your study, and communicate information about the study to others.
Anxiety study: Researchers used a version of the placebo effect (being given a sugar pill and thinking it is a
drug) on 25 people who have social anxiety disorder. The participants had to give a speech at the start and end
of an 8-week period during which they took the pill they thought was medication for their anxiety.
• 10 people improved dramatically (by test scores that rate anxiety and brain scans of activity in their
amygdala, the “fear” region of the brain). 15 people made no improvement
• All participants were also tested to see what allele they had of the tryptophan hydroxylase-2 gene, which
is required to synthesize serotonin. A particular allele of this gene has been previously associated with
“calmness”.
• 8 of the 10 people who improved dramatically had this particular allele (the “calmness” allele), while 0
of the 15 people who did not improve in this placebo trial had this allele.
Questions
1. What can you conclude from this study?
2. What can you not conclude based solely on the evidence provided?
3. Does this study provide correlative or cause and effect type of evidence?
4. What are the problems with this study?
5. What could you do to make it better, or what kind of a study could you design to improve the strength of a
conclusion about a certain gene’s involvement in anxiety.
Alcohol consumption study
The goal of this study was to actively alter the levels of D2 receptor in an animal’s brain and look at the effects.
In this study, 15 genetically identical mice were given access to alcohol, which they could drink as they desired.
An adenoviral vector was used to deliver the dopamine D2 receptor (DRD2) gene directly into the nucleus
accumbens of these rats. Scientists were then able to measure the amount of the D2 receptor present in the
brain: an increase of 50% was seen within four days of injection. By day 10 the level has dropped back to
normal.
The 50% increase in D2 resulted in an average of 70 percent drop in alcohol consumption by the
animals. Their alcohol consumption returned to normal by day 10.
Questions
1. What can you conclude from this study?
2. What can you not conclude based solely on the evidence provided?
3. Does this study provide correlative or cause and effect type of evidence?
4. What are the problems with this study?
5. What could you do to make it better, or what kind of a study could you design to improve the strength of a
conclusion about a certain gene’s involvement in anxiety.
Find out more about D2 receptors and other markers for addiction.
1. Go to Science Daily (www.sciencedaily.com) and search for articles on dopamine receptors and alcohol
2. Go to The Online Mendelian Inheritance of Man site, “OMIM”: a great place to search for information
about such genes: http://www.ncbi.nlm.nih.gov/omim
A “markers for addiction” gene panel scans people’s DNA for variants that are associated with addiction
tendency. The eleven genes encode proteins that are ion channels, cell surface molecules, receptors, enzymes,
or cell adhesion molecules. The markers are: CHRNA3, CHRNA5, CHRNB3, CLCAI, CTNNA3, GABRA4,
KCNJ6, NRXN1, TRPC7.
How might any of these alleles increase the possibility of addictive behavior?