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CHAPTER 5
Drugs, Addiction,
and Reward
Addiction
Addiction
• Societal definition:
– not a scientific definition
– Obsession, compulsion, or excessive physical
dependence or psychological dependence
• E.g., drug addiction, alcoholism,
compulsive overeating, problem gambling,
computer addiction, pornography, etc.
• Focus is on deleterious behavior
Addiction
• Scientific definition of Addiction: A state in which the
following occurs:
– Physical dependence: the body relies on a substance for
normal functioning and develops
– Withdrawal: When the drug or substance on which
someone is dependent is suddenly removed, physical
symptoms occur.
– Drug tolerance. More and more of the drug is required
to achieve the same effect
• Common usage includes psychological dependence, but
brain doesn’t recognize this distinction
Addiction
• Addiction and withdrawal take place in
different parts of the brain and are independent
of each other.
• The ventral tegmental area (VTA) and
nucleus accumbens (Nac) is suggested to be
involved in addiction
• Periventricular gray area (PGA) produces
classic signs of withdrawal.
Addiction
• Not mean that addicts never take drugs to
avoid withdrawal symptoms
– E.g., one type of alcoholism is avoidance of
painful experiences via alcohol
– But not avoidance of alcohol itself
• Means that withdrawal is not necessary
for addiction and avoidance of withdrawal is
not an explanation of addiction.
Addiction pathways
Addiction involves
Dopaminergic pathway
• Mesolimbicortical Dopamine System
– Major reward system of the brain
– Many drugs (especially stimulants) mimic effects of normal
reward reactions
– Pathway begins in the midbrain (mesencephalon) and
projects to the limbic system and prefrontal cortex.
• The most important structures in the system:
– Nucleus Accumbens (NAc)
– Medial forebrain bundle (MFB)
– Ventral tegmental area (VTA)
Dopaminergic
Reward pathways
• Reward:
– Defined by your book: positive effect an object or condition – such as a
drug, food, sexual contact, and warmth – has on the user
• Behaviorists: Any consequence which, when delivered
contingently, results in an increase in the continent response
• Dopamine serves as a feedback signal: do that behavior again,
you got something!
– Seeking behavior
– Behavioral momentum: Do whatever got you the reward
Dopaminergic
Reward pathways
• General Reward System: includes brain responses to:
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Feeding: Any behaviors related to feeding
Drinking: any behaviors related to drinking
Sexual behavior: Any behaviors related to sex (including maternal)
Drug effects and drug related behavior that mimic these functions
• Includes Conditioned Rewards
– Rewards that are learned, not innate
– Money, family and relationships, value of a job
– Experience is required to learn these are reinforcers
Reward and the
Dopaminergic pathway
• Schultz (2005) and others show:
– Dopamine is not released as a reward
– Dopamine is a motivating neurotransmitter- produces increases in
locomotion, action behavior that is oriented towards reward
• Study with Monkeys:
– CS (tone) – US (food):
• DA initially released upon presentation of the food
• DA release moves to predictive CS of tone
– Add a lever pressing requirement: S+ (tone): lever press food
• Now DA is released JUST BEFORE movement of arm towards lever
• DA is released as motor response is PLANNED in the prefrontal area
Reward and the
Dopaminergic pathway
• Thus: when dopamine released, body moves towards or
continues doing whatever it was doing to keep getting that
“Reward”
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–
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Jacob Panskepp: Dopamine serves to invoke “seeking behavior”
We seek reinforcing stimuli (innate or conditioned)
When we seek, DA is released, which keeps us seeking
If the reward stops coming, behavior decays, DA drops, seeking stops
• Addictive substances reset our thermostat for seeking behavior
– Increases it to artificially high levels
– DA release from drug is many, many times greater than that released
for natural reward.
– Normal reinforcers aren’t worth seeking, in comparison to Cocaine, etc.
Reward and the
Dopaminergic pathway
• General DA reward system serves as feedback system that
identifies
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–
–
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Need to continue or shift behavior depending on reward situation
IF get a reward…keep doing that behavior
IF NOT get a reward: change behaviors
Helps select the appropriate response for the situation
• Learn that going to class increases likelihood of a good grade
– Good grades associated with positive affect and attention from others
– Learn to seek good grades
– Dopamine is released during behaviors that are likely to increase the
probability of a good grade
– IF you stop getting good grades for going to class….class attendance
drops
Changing behavior with
DA agonists
• Release of Dopamine = seeking behavior
– Can demonstrate this by artificially releasing dopamine in presence of
various stimuli
– What happens to animal when we electrically stimulate neurons to
produce DA release?
• Electrical stimulation of the brain (ESB),
– Stimulate the Nucleus accumbens
– Result: Animals press a lever or engage in high rates of locomotion
immediately after receiving stimulation
– What they do depends upon setting:
• If there is a lever, they press it
• If there is an open field, they run
• Why? DA release elicits “search” or seeking behavior
Changing behavior with
DA agonists
• A reinforcer is any object or event that increases the
probability of the response that precedes it
– Thus, must keep doing the behavior that got you the reinforcer
– DA maintains ongoing responses or kicks you into movement behaviors
that increase likelihood of reward.
• Virtually all the abused drugs increase dopamine levels in the
nucleus accumbens
•
•
•
Mimic the effect of natural reinforcers
But at much higher DA levels in the synapse
Again, may reset the “thermostat” for reinforcement to artificially high
levels.
• Question for treatment: CAN we reset brain DA levels
to normal levels?
Changing behavior with
DA agonists
• Think of symptoms of stimulant abuse/addiction:
– Lots of motor movement
– Lots of “seeking” behavior: Gotta get that drug!
• Lots of perseverative motor behavior:
– Nose wiping, Tics, Perseveration
– Also overstimulating DA Basal Ganglia motor system
• Paranoia is highly similar to schizophrenia
• Why? Too much dopamine is overstimulating circuits,
cognitive areas of brain are hyperstimulated.
Changing behavior with
DA agonists
• Addictive behavior:
– What got you these rewarding feelings- the drug
– What do to keep these feelings- get more drug
– What does the drug make you feel like?....getting more drug
• And, because you have replaced normal DA levels,
now you will engage in seeking behaviors to
maintain those levels!
– Again, normal rewards are just not as reinforcing as drug
– Drug releases so much more DA than normal rewards
– Habituate/reset brain thermostat for higher DA amounts
Reward deficiency
syndrome
• Chronic drug users show diminished DA release from
DA receptors
• May be the individual, and not the addiction
– Lower levels of D2 autoreceptors
– Those with high number of D2 autoreceptors find DA drugs unpleasurable
– D2 autoreceptors help regulate general DA tone in synapse, regulate
reuptake and production of DA
• Reward deficiency syndrome:
– may be that DA-drug addicts have insufficient receptors to respond to DA,
– need more DA to get same effect
– Related to thrill seeking behavior: Thrills = DA surge
Addiction = learning
• Addiction = learning process
– Learning what predicts increase in DA
– For most of us: Natural or conditioned rewards for appropriate
behavior
– For addicts: learn to seek drugs that stimulate the DA system.
• Learning produces changes in the brain
– Forms new memory circuits for related stimuli
– Allows two events or stimuli to be linked predictively
– Addiction produces same changes in neurons as normal learning
• These processes include the Step down reflex and compensation
Compensatory response
• Drug = release of DA: US(drug) UR(drug effects)
• Stimulus (CS) predicts drug that releases DA:
CS(cue US(drug)  UR(drug effects)
• E.g.: Morphine decrease in pain, HR, respiration, feelings
of euphoria
• Needle, friends, location-- morphine-(all of above)
increase in pain, HR, respiration
Step down reflex
• Stimulus predictors: Anticipation reward  DA release
• BUT Body prefers homeostasis: no sudden changes,
maintain level
– CS(cue US(drug) UR(drug effects)
CR(decrease DA release in anticipation of drug DA release)
Thus: body REDUCES dopamine in ANTICIPATION of
increase in DA
Compensation:
tolerance and withdrawal
• Body REDUCES dopamine in ANTICIPATION of increase
in DA mimic of drug
– No longer get same effect for drug (or activity)
– Must take more/engage in more
– This is called tolerance
• If stop taking the drug, no step-down reflex or compensation
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Now, reduction in DA in anticipation, but no DA comes
Now have too little DA: shaky, motor tremors, etc.
This is called withdrawal:
Setting cues are critically important
PET scans are shown at two depths in the brain. Notice the increased
activity during presentation of cocaine-related stimuli. Frontal areas (DL,
MO) and temporal areas (TL, PH) are involved in learning and emotion.
Evidence for Addiction?
• Prefrontal release produces a compulsive focus on
drugs at the expense of other reinforcers
– Allows formation of “memory circuits” for compulsive
behavior
• Glutamate release cranks up the drive to engage in
drug seeking.
– Further stimulates the DA circuitry and memory paths
Evidence for Addiction?
• Becomes an endless loop!
– Seeking behavior is reinforced
– Connections between thinking part of brain and seeking part of brain
made stronger
– Seeking  drug seeking - drug- seeking………
• Predictive stimuli allow this circuit to engage
– Engaging in the seeking behavior strengthens the relationship between
the predictive stimuli and seeking
– Every time the addict uses it reinforces the addiction!
Evidence for Addiction?
• Nora Volkow, et al.’s work: How do people transition
from controlled drug use to compulsive drug intake?
• Found that addiction involves pathological changes in
communication between prefrontal cortex and the
nucleus accumbens
– Learning system is “hijacked”
– Learning about drugs rather than normal environmental
events
– Mesolimbocortical pathway becomes sensitized to drug
rather than environmental events.
Evidence for Addiction?
• Addict in recovery:
– Attempt to extinguish learned response to drugs
– Reset brain to react to normal rewards
• Addict returns to drug taking when
– Stress or drug-related stimuli trigger increases in dopamine
release in the prefrontal cortex and glutamate release in the
nucleus accumbens.
– Stimulates those memory circuits for that seeking behavior
– IF memory for addictive behavior is stronger than newly
learned sober behaviors, addictive behaviors result
Treating Addiction
• Agonist treatments replace an addicting drug with another
drug that has a similar effect.
– Opiate addiction is often treated with a synthetic opiate called
methadone.
– Is simply substituting one drug for a another, albeit safer, drug
• This tends to be ineffective:
– Not resetting the brain
– Often have to continue to increase doses of methadone because of
tolerance effects
– If addict highly likely to return to the “better” drug
Treating Addiction
• Antagonist treatments involve drugs that block the effects of
the addicting drugs.
– Drugs that block opiate receptors are used to treat opiate addictions and
alcoholism because they reduce the pleasurable effects of the drug.
– Nalaxone for opiate addiction
– Antabuse for alcohol
– Moderately successful IF patient is compliant
– Causes major side effects…most patients non compliant
• Another experimental strategy is to interfere with the
dopamine reward system.
– Baclofen reduces dopamine activity in the ventral tegmental area by
activating GABAB receptors on dopaminergic neurons.
The two rats received the same amount of alcohol, but the one on the right
received a drug that blocks the effect of alcohol at the GABAA receptor
TREATMENT OF Addiction
• Aversive treatments cause a negative reaction when the
person takes the drug.
– Antabuse interferes with alcohol metabolism, so drinking alcohol
makes the person ill.
– Punish person for taking drug
• BUT: aversive system is the Periaqueductal gray area (PGA)
– NOT part of addiction system
– Now have avoidance AND addiction
• Antidrug vaccines
– synthetic molecules that resemble the drug
– modified to stimulate the animal’s immune system
– make antibodies that will degrade the drug: drug no longer effective
TREATMENT OF Addiction
• Behavioral Treatments: most effective
– Teach the client the process of addiction and understanding of their
disease
– Unlearn the addiction
– Teach compensatory behaviors for dealing with stress
– Teach compensatory behaviors that interfere with drug-seeking
behavior
• Reform the circuits:
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Re-establish natural reinforcers as reinforcing
Unpair drug predictors with seeking system
Build new social and coping skills
The longer one has been an addict = longer to relearn
The Role of Genes
in Addiction
• If genetics plays such an important role in addiction,
just what is inherited?
– Most research on the genetics of addiction implicates various
neurotransmitter systems.
– Appears to be a syndrome or related group of dysfunction
– E.g., reward deficiency syndrome
• Addicts correlated with individuals who have family
members with
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Schizophrenia, bipolar disorder, depression
ADHD and related disorders
Autism and autism-spectrum disorders.
Seems to be general difference in DA and 5HT systems
The Role of Genes
in Addiction
• Dopamine is one of the factors differentiating addictive
from normal behavior.
– Several alleles, or alternate forms, or the gene responsible for
the development of the D2 subtype of dopamine receptor.
– These various alleles are associated with alcoholism, cocaine
dependence, stimulant abuse, and multiple addictions.
• May be a propensity or predisposition to addiction
– Not causal but increased likelihood
– Best predictor of drug abuse in families: Lack of good coping skills and
a positive and supportive social network
The Role of Genes
in Addiction
• Wait: Not so simple!
• Serotonin is also involved in drug abuse in general
– Also involved in mood regulation and anxiety regulation
– Critical for sexual behavior
– Linked with aggression
– Also highly involved in the regulation of bodily rhythms
and food and water intake.
• Also need to consider role of GABA and Glutamate!
The Role of Genes
in Addiction
• Bottom line: An individual may have a
predisposition towards addiction
– Familial predisposition
– Individual life experiences
• Stress bring out or turns on different coping mechanism
– Individuals with strong coping mechanisms avoid addiction
– Those without more likely to become addicts
• Best way to avoid: reduce stress; avoid situations with drug
availability and develop good coping skills!
A Societal comment on drug
usage from the onion!
• And now for something absolutely silly!
• http://www.theonion.com/content/video/fda_approves_de
pressant_drug_for