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Addiction
Chapter 15
Drug Addiction and the
Brain’s Reward Circuits
Chemicals That Harm with
Pleasure
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Basic Principles of Drug Action
• Psychoactive drugs – drugs that influence
subjective experience and behavior by acting on
the nervous system
• Drug administration – route of administration
influences the rate at which and the degree to
which the drug reaches its site of action
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Drug Administration
• Ingestion – oral route
– Easy and relatively safe
– Absorption via digestive tract is unpredictable
• Injection – bypasses digestive tract
– Subcutaneously (SC) – under the skin
– Intramuscularly (IM) – into large muscles
– Intravenously – into veins – drug delivered directly to
brain
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Drug Administration
• Ingestion
• Injection – SC, IM, IV
• Inhalation – tobacco and marijuana
– Absorbed through capillaries in lungs
• Absorption through mucous membranes
– Nose, mouth, rectum
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Mechanisms of Drug Action
• In order for a psychoactive drug to have an
effect, it must get to the brain – it must pass
through the blood-brain barrier
• Action of most drugs terminated by enzymes in
the liver – drug metabolism
• Small amounts may also be excreted in urine,
sweat, feces, breath, and mother’s milk
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Drug Tolerance
• Decreased sensitivity to a drug as a
consequence of exposure to it
– Shift in the dose-response curve
• Cross tolerance – exposure to one drug can
produce tolerance to similar drugs
• Tolerance often develops to some effects and
not others
• More than one form of tolerance
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Drug Tolerance
• Metabolic
– Less drug is getting to the site of action
• Functional
– Decreased responsiveness at the site of
action - fewer receptors, decreased efficiency
of binding at receptors, receptors less
responsive
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Physical Dependence
• Indicated by occurrence of withdrawal
– Seen when drug use is terminated
– Symptoms are the opposite of the drug’s effects
– Body has made changes to compensate for drug’s
presence – functions normally with the drug present
– Severity varies with drug and pattern of use
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Addiction: What Is It?
• “Addicts” are those who continue to use a
drug despite its adverse consequences
• Addiction and physical dependence are
not the same thing
• While they may co-occur, each can exist
independently
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Learning in Tolerance and
Withdrawal
• Contingent drug tolerance
– Tolerance only develops to drug effects that are
experienced
• Conditioned drug tolerance
– Maximal tolerance effects are seen in the environment
in which a drug is usually taken
• Conditioned withdrawal effects
– Withdrawal elicited by drug-related cues
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Conditioned Tolerance and
Withdrawal
• Situational specificity of drug tolerance is welldocumented
• Environmental cues associated with drug-taking
become conditioned stimuli that elicit
conditioned compensatory responses, producing
tolerance prior to drug use or withdrawal in the
absence of the drug
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5 Commonly Abused Drugs
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Tobacco
Alcohol
Marijuana
Cocaine
Opiates
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Tobacco
• Nicotine – major psychoactive ingredient
• About 70% of those who experiment with
smoking become addicted
• Only about 20% of attempts to stop are
successful
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Alcohol
• A depressant
• High heritability estimate for alcohol addiction
- ~55%
• Metabolic and functional tolerance develops
• Attacks almost every tissue in the body
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Effects of Chronic Alcohol
Consumption
• Severe withdrawal – 3 phases
– 5-6 hrs post-drinking: tremors, nausea, sweating,
vomiting, etc.
– 15-30 hrs: convulsive activity
– 24-48 hrs: delirium tremens – may last 3-4 days
• Korsakoff’s syndrome
• Cirrhosis
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Alcohol and the Brain
• Reduces flow of Ca++ into neurons
• Interferes with 2nd messenger systems
• Disrupts GABAergic and glutaminergic
transmission
• Triggers apoptosis
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Marijuana
• Cannabis sativa – common hemp plant
• THC – primary psychoactive constituent –
although over 80 others are present
• High doses impair short-term memory and
interfere with tasks involving multiple steps
• Addiction potential is low
• Negative effects are far less severe than those
associated with alcohol and tobacco
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Adverse Effects of Heavy
Marijuana Use
• Respiratory problems – cough, bronchitis,
asthma
• Single large doses can trigger heart
attacks in susceptible individuals
• No evidence that marijuana causes
permanent brain damage
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Medicinal Uses of Marijuana
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Treat nausea
Block seizures
Dilate bronchioles of asthmatics
Decrease severity of glaucoma
Reduce some forms of pain
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THC
• Fat-soluble
• Binds to receptors in basal ganglia,
hippocampus, cerebellum, and neocortex
• Endogenous ligand is anandamide
• Function of anandamide is not known
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Stimulants
• Increase neural and behavioral activity
• Cocaine and its derivatives – commonly abused
• Crack – a potent, cheap, and smokable form of
cocaine
• Cocaine is an effective local anesthetic
– Synthetic analogues procaine and lidocaine used
today
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Cocaine
• Cocaine binges or sprees may lead to cocaine
psychosis
– Looks like paranoid schizophrenia
• While tolerance may develop to some effects of
cocaine, sensitization is seen to motor and
convulsive effects
• Although highly addictive, withdrawal is relatively
minor
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Amphetamine
• AKA “speed” – another abused stimulant
• Effects are comparable to those of cocaine –
also can produce psychosis
• MDMA (ecstasy) – a relative of amphetamine
• Evidence suggests that stimulants are
neurotoxins
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Ecstasy
• Studies of lab animals find that MDMA has toxic
effects on serotonergic and dopaminergic
neurons
• But are the doses used in studies comparable to
what humans use?
• Human studies do find abnormalities of
serotonergic function and deficits in memory,
mood, and psychomotor tasks
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Opiates: Heroin and Morphine
• Morphine and codeine obtained from the opium poppy
• Opiates – these drugs and others with similar
structures or effects
• Medicinal uses
– Analgesics (painkillers)
– Treatment of cough and diarrhea
• High risk of addiction
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Factors Increasing Opiate
Popularity
• China’s ban of tobacco smoking led to opium
smoking
– More addicting than eating opium
• Isolation of morphine
– Opium’s most potent constituent
• The hypodermic needle
– During the Civil War morphine addiction came to be
known as “soldiers’ disease”
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U.S. Opiate History
• Readily available in a variety of “potions” until
1914
• Harrison Narcotic Act (1914)
– Illegal to sell or use opium
– Heroin, a synthetic opiate, was still legal
• Structure similar to morphine, but better able to cross the
blood-brain barrier
• More addictive
• Heroin illegal as of 1924
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Opiate Addiction
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Drawn to use by the rush following IV injection
Tolerance and physical dependence develop
Desire to avoid withdrawal adds to motivation to use
Although highly addictive, direct health hazards are
relatively minor
• Many health hazards related to use of needles
• Severity of withdrawal has been exaggerated
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Treatment for Heroin Addiction
• Opiates bind to endorphin receptors
• Methadone binds to these receptors
– Produces less pleasure
– Administered orally
– Prevents withdrawal
• Buprenorphine – similar to methadone but longer lasting
• Substituting a less dangerous drug for the abused drug
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Reducing Drug Abuse
• Current approaches are not effective.
• What recommendations would you
make to decrease the incidence of
drug abuse?
• Which abused drugs should we be
most concerned about?
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Biopsychological Theories of
Addiction
• Physical-Dependence Theory –
– Use continues to avoid withdrawal
• Why relapse after detoxification?
• Why begin use?
• Why does addiction develop to drugs that do not produce
severe withdrawal?
• Positive-Incentive Theories
– Use continues due to craving for drug effects
– Supported by research
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Causes of Relapse
• Stress
– Drug use as a coping mechanism
• Priming
– A single exposure leads to a relapse
• Environmental cues
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Pleasure Centers of the Brain
• Brain circuitry exists that makes certain
behaviors pleasurable
• Many species will work for stimulation of
brain “pleasure centers”
• Discovered by Olds and Milner
• Drug use may be reinforced by acting on
this circuitry
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Mesotelencephalic Dopamine (DA)
System and Self-Stimulation
• DA neurons projecting from the midbrain to
areas in telencephalon
• Nigrostriatal pathway
– Substantia nigra > Dorsal striatum
• Mesocorticolimbic pathway
– Ventral tegmental area > cortical and limbic sites
– Involved in reward
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Mesocorticolimbic Pathway and
Reward
• Self-stimulation sites that do not contain DA
neurons project here
• Increase in DA release seen here in selfstimulation studies
• DA agonists tend to increase self-stimulation and
antagonists to decrease
• Lesions here disrupt self-stimulation
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Neural Mechanisms of Motivation
and Addiction
• How do drugs act on existing reward circuitry to
motivate addicts to continue to use?
• Asking animals what they like – necessary to
explore positive-incentive theories
– Drug self-administration
– Conditioned place-preference
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Behavioral preference tests
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Dopamine and Drug Addiction
• DA’s role suggested by self-stimulation
studies
• DA antagonists interfere with selfstimulation and reduce the reinforcing
effects of food
• Nucleus accumbens appears to play a
primary role
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Nucleus Accumbens (NA) and Drug
Addiction
• Animals self-administer microinjections of addictive
drugs into NA
• Microinjection of drugs into NA produce conditioned
placed preferences
• Lesion NA or ventral tegmental area – no drug selfadministration or drug-related place preference
• Both self-administration of addictive drugs and natural
reinforcers result in increased dopamine in the NA
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DA and Addiction
• Role is well-established
• Cocaine acts as a DA agonist by binding to DA
transporters and blocking reuptake
• Addicts only report a high when cocaine is effectively
blocking DA reuptake, increasing extracellular dopamine
• IV amphetamine study – euphoria reported correlated
with DA levels in nucleus accumbens
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Addiction
• While pieces of the puzzle are understood,
many questions remain
• Some studies suggest that DA is involved
in expecting reward, as opposed to reward
itself
• Considering what we do know, how can
addiction best be explained?
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