Chapter 15: Drug Addiction and the Brain's Reward Circuits

o Pharmacological: Pertaining to the scientific study of drugs

o Over 60 million people in the United States are addicted to alcohol, nicotine or both
5.5 million people are addictedto illegal drugs
Many millions addicted to prescription drugs
15.1: Basic Principles of Drug Action
o Drug Administration and Absorbtion
o Psychoactive Drugs: includes all substances that alter subjective experience and behaviour by
acting on the nervous system.
o The route of drug administration affects two things
The speed at which the substance is able to reach the site of action
Which site of action it reaches
o 4 methods of drug administration:
Oral ingestion
Injection
Inhalation
Mucous Membranes
o Oral Ingestion
Eating, drinking or otherwise swallowing the substance
Once swallowed, the substance is dissolved and broken down in the fluids of the
stomach
Dissolved substance is carried to the small intestine
Substance is absorbed into the bloodstream from the small intestine
Some substances readily pass through the lining of the stomach, bypassing the small
intestine all together
o Alcohol is an example of a drug that passes through the lining of the stomach
Advantages
Easiest
Safest
Preferred method of administration for most substances
Disadvantages
Drug metabolism in the digestive tract can be unpredictable
o Amount of substance absorbed is influenced by particularly hard to predict factors
such as how much food is in the stomach and what type.
Slower method of administration
Some substances are not able to be efficiently administered using this method
o Some substances are not easily absorbed by the digestive tract
o Some substances get broken down into inactive metabolites instead of being carried
in their psychoactive form to the central nervous system
o Metabolites: Breakdown products of the body's chemical reaction
o These substances must be administered using other methods
o Injection
The method of injection bypasses the digestive tract
Prevalent in medical practice

Subcutaneous (SC): Beneath the skin into fatty tissue

Intramuscular (IM): Into large muscles
Intravenous (IV): Injection directly into veins at points where they are directly beneath the
skin
in this method of drug administration, the drug is delivered directly to the brain.
o For this reason, many addicts prefer this route of administration
Advantages
Fastest method of administration
Strong reaction to the substance in most patients
Predictable reaction to dosing
o Elimination of most difficult to estimate factors
Disadvantages
Little or no opportunity to counteract overdose effects
Little or no opportunity to counteract impurity or drug interaction effects
Little or no opportunity to couneract allergic reactions to injected substances
Many addicts develop scar tissue, infections and collapsed veins at points where large
veins are close to the skin
o Inhalation
Used for administering tobacco and cannabis
Also used for the administration of medical anaesthetics
Drug is absorbed through the capilleries in the lungs
Inhalation: Route of drug administration where by the user breathes in the active ingredient
and it is absorbed through the capilleries of the lungs.
Advantages
Faster than ingestion
Disadvantages
Difficult to precisely regulate the dosage
Damage can be caused to the lungs if certain substances are used chronicly
o Absorbtion through Mucous Membranes
Absorbed through the nose, mouth or rectum
Used to administer cocaine
Damages mucous membranes used to absorb the drug
Drug Penetration of the Central Nervous System
o In order for any drug to have a psychoactive effect, the active ingredient must reach the brain.
Substances are carried to the central nervous system by the blood
In order for any substance to reach the brain it must cross the blood brain barrier
Blood-Brain Barrier: The mechanism that keeps certain toxic substances in the blood from
passing into brain tissue
Acts like a protective filter
Mechanisms of Drug Action
o Some drugs act diffusely on many neural membranes throughout the central nervous system
Examples include alcohol and general anesthetics
o Other modes of drug action include
Binding to receptors at particular synapses
Influencing the synthesis, release, transport or deactivation of neuotransmitters

Influencing the chain of chemical reactions elicitted in postsynaptic neurons by the

activation of their receptors
Drug Metabolism and Elimination
o Most drugs deactivated by enzymes in the liver during the process of drug metabolism
o Small amounts may also be excreted in the sweat, breath, mother's milk, urine and feces
o Drug Metabolism: The conversion of a drug from its active form to its non active form
Most of the time this process breaks substances down into constituent components which
are unable to cross the blood brain barrier
Drug Tolerance
o Drug Tolerance: A state of decreased sensitivity to a drug that develops as a response to
exposure to the drug
A shift in the dose withdrawal curve to the right
In tolerant subjects, the same dose has less effect than when administered to non-tolerant
subjects
In tolerant subjects, a larger dose is required to elicit the same effects as in non-tolerant
subjects
o Cross Tolerance: Tolerance to the effects of one drug that develops due to exposure to another
drug that acts on the same mechanism.
o It is possible to become tolerant to some effects of a drug but not others
o Often tolerance to some aspects of the drug develop while sensitization to other aspects of the
drug develop
o Drug Sensitization: An increase in the sensitivity to a drug effect that develops as a result of
exposure to a drug
Also called "Inverse Tolerance"
o Metabolic Tolerance: Tolerance that results from a reduction in the amount of a drug getting to
its site of action.
o Functional Tolerance: Tolerance resulting from a reduction in the reactivity of the nervous
system (or other sites of action) to a drug.
May result from having fewer receptors, having decreased efficiency at binding to receptors
or existing receptors being less responsive to the same level of activation
o There is no single mechanism that controls or explains all tolerance. Examples of tolerance
mechanisms in common psychoactive substances
Substance may reduce the number of receptors for that neurotransmitter
Substance may decrease the efficiency with which the effected neurotransmitter binds with
the receptor
Substance may diminish the effect of a neurotransmitter binding on the receptor
Some of the mechanisms involve an alteration of gene expression
Drug Withdrawal and Effects of Physiological Dependence
o Withdrawal Syndrome: The illness brought on by the elimination from the body of a drug on
which the person is physically dependent.
Brought on by cessation of a drug to which an individual was physically dependent
Physically Dependent: Being in a state in which the discontinuation of a drug will cause
withdrawal syndrome.
Symptoms are opposite to the positive symptoms experienced while on the drug
Ie. Cessation of anticonvulsants causes convulsions, cessation of sleeping pills causes
insomnia

The fact that the symptoms of withdrawal syndrome are opposite to the effects of the
drug suggest that the neural mechanism responsible for developing tolerance is also
responsible for withdrawal syndrome
This theory explains that the body conditions itself to the presence of the drug so as to
function normally while the substance is present. When the substance is suddenly no
longer present, the neural changes manifest themselves as withdrawal symptoms until
the body rehabituates itself to the absense of the substance
The body makes changes to its normal functioning in order to compensate for the
continuous presence of a foreign substance.
When that substance is present, the body continues to function normally
Severity of withdrawal syndrome varies based on a few factors
What drug is being withdrawn from
How often the drug is used
How high the dosage is before cessation
How quickly the drug is terminated (ie. Tapering down produces less, but longer
withdrawal, than stopping the substance all together all at once)
Addiction: What is it?
o Addict: Habitual drug user who continues to use a substance despite its adverse effects on their
health and social life and despite repeated efforts to stop using the substance.
Addiction can occur simultaneously or separately from withdrawal
After the withdrawal syndrome due to physical dependence has ended, addicts still crave the
drug
Not all habitual drug users are addicts
The idea that addiction is interchangeable with dependence is flawed
Evidence shows that addicts who are no longer feeling symptoms of withdrawal may
still crave the substance
Drugs are not the only behaviour to which human beings can be addicted
Mechanisms for gambling, food and sexual addictions may be the same underlying
neural mechanisms behind drug addiction

15.2: Role of Learning in Drug Tolerance

o Contingent Drug Tolerance
o Contingent Drug Tolerance: Drug tolerance that develops as a reaction to the experience of
the effects of exposure to the effects of the drug rather than to drug exposure alone
Drug tolerance develops only to those effects which have been personally experienced
Tolerance does not develop to effects of the drug the individual has not experienced, even if
they have taken the drug
Contingent drug tolerance has been demonstrated using many substances
Contingent drug tolerance has been shown in humans
o Before-and-After Design: The experimental design used to demonstrate contingent drug
tolerance.
The experimental group receives the drug before each of a series of behavioural tests, and
the control group is exposed to the drug after each test.
Two groups of rats received the same dosage of alcohol for the duration of the experiment.
One group was given mild convulsions before receiving alcohol and the other group was
given mild convulsions after receiving alcohol. Only the group that received the alcohol first

(and thus, experienced its anti-convulsive effects) became tolerant to alcohol's anticonvulsive effects.
O Conditioned Drug Tolerance
o Conditioned Drug Tolerance: Tolerance effects that are maximally expressed only when a
drug is administered in the situation in which it has been previously administered.
Situational specificity of drug tolerance is well documented
Addicts are far more likely to overdose in an unfamiliar setting
Both cues from without and within the body can trigger a conditioned tolerance in the
presence of the drug, or conditioned withdrawal in its a sense.
Conditioned drug tolerance has been thoroughly investigated
o Hypothermic:
o Situational Specificity of Drug Tolerance: Tolerance to a given substance that is maximally
counteractive in any environment in which the drug was previously experienced
Each drug administration acts essentially as a Pavlovian conditioning trial where the various
environmental stimuli that predict the usage of the substance become conditional stimuli
and the effects of the drug are uncondtional stimuli
o Overdose:
o Conditioned Compensatory Response: Physiological responses opposite to the effects of a
drug that are thought to be elicited by stimuli that are regularly associated with experiencing the
drug effects.
Withdrawal syndrome triggered by the presence of stimuli associated with taking a drug
o Exteroceptive Stimuli: Stimuli that arise from outside the body
o Interoceptive Stimuli: Stimuli that arise from within the body.
o Drug Sensitization: An increase in sensitivity to a drug that develops as a result of exposure to
the drug.
Can also be situation specific
o Drug withdrawal syndrome and conditioned compensatory responses are different
Withdrawal syndrome occurs with cessation of a drug that is normally present continuously
in the body
Conditioned responses are triggered by cues that reliably predict substance use in the
absense of the drug
Thinking About Drug Conditioning
o
15.3: Five Commonly Abused Drugs
O Tobacco
o When tobacco smoke is inhaled, nicotine and approximately 4000 other chemicals are absorbed
through the lungs
o Nicotine: The major psychoactive ingredient of tobacco
Nicotine is one of the most highly addictive substances currently known
70% of individuals who experiment with smoking nicotine become addicted
10% addiction rate of alcohol
30% addiction rate for heroin/opiates
More addictive than both alcohol and heroin!
Only 20% of attempts to stop smoking are successful
Addiction to nicotine develops in few weeks

 Nicotine addiction has a major genetic component (Heritability estimate of 65%)

o Tar: The collection of non-nicotine chemical compounds that are inhaled and absorbed in the
lungs along with nicotine when smoking a cigarette
o Tobacco is the leading cause of preventable death in Western Countries
o Non-smokers and smokers report very different effects to smoking due to tolerance effects that
have set in for smokers
Non-smokers report a combination of nausea, vomitting, coughing, sweating, abdominal
cramps, dizziness, flushing and diarrhea
Smokers report feeling calmer, more alert and less hungry after a cigarette
o Withdrawal effects from smoking include
Depression
Anxiety
Restlessness
Irritability
Constipation
Difficulties sleeping
Difficulties concentrating
o Smoker's Syndrome: The chest pain, laboured breathing, wheezing, coughing and heightened
susceptibility to infections of the respiratory tract common in smokers.
o Long-term effects of smoking include smoker's syndrome, increased susceptibility to infections
and illnesses of the respiratory system and various lethal lung disorders
o Bronchitis: Chronic inflammation of the bronchioles of the lungs
o Emphysema: Loss of elasticity of the lungs due to chronic irritation
o Smoking leads to a variety of cancers
Lung cancer has been the must publicized cancerous effect of smoking
Larynx/Voice box
Mouth
Esophagus
Pancreas
Bladder
Kidneys
Stomach
o Smokers are also at higher risk for cardiovascular diseases which culminate in heart attack or
stroke
o Quitting smoking by the age of 40 adds an average of 9 years to an individual's lifespan
Smokers who quit before the age of 30 live almost as long as individuals who never smoked
o Levels of tension in smokers are higher overall than in non-smoker's
Tension levels are normal while having a cigarette
Tension levels rise higher than normal during interval between cigarette smoking
Relaxing effect smoker's report feeling subjectively is a temporary reversal of the tension
caused by the smoker's addiction to nicotine
Smokers are more likely than non-smokers to experience panic attacks
o Buerger's Disease: A condition in which the blood vessels, especially those supplying the legs,
are constricted whenever nicotine enters the bloodstream, the ultimate result being gangrene
and eventual amputation.
Occurs more commonly in men than women

Surgeons and doctors often warn patients that if they give up smoking, the adverse effects
on their legs will stop and they will not have to experience amputation (or further
amputation)
It is not uncommon, however, for patients to be unable to give up smoking even after their
second, third and fourth amputation operation
o Individuals who work or live with smokers are more likely to develop heart disease and cancer
than individuals who live and work with non-smokers
o Teratogen: A drug or other chemical that causes birth defects.
Nicotine is a teratogen
Smoking during pregnancy increases the likelihood of
Miscarriage
Stillbirth
Early death of the baby
Nicotine levels in the blood of babies breastfed by smoking mothers is often as high as the
level of nicotine in the blood of the mother
o Treatment for nicotine addiction are only mildly effective
O Alcohol
o Alcohol is a depressant
At moderate to high doses, alcohol depresses neural firing
At low doses, alcohol can increase neural firing
Low doses may facilitate social functioning
o Alcohol is involved in over 3% of all deaths in the United States
o Approximately 80 000 people die each year because of the consumption of alcohol
o Heritability estimate for alcoholism is approximately 55%
Several genes have been identified as associated to inherited alcoholism
o Consumers of moderate amounts of alcohol experience
Cognitive impairment
Perceptual impairment
Verbal impairment
Motor impairment
Loss of self control
Risk of death due to respiratory depression at blood alcohol levels over 0.5%
o Both metabolic and functional tolerance develop to the frequent consumption of alcohol
Livers of drinkers process the substance more quickly than the livers of non-drinkers
Increase in metwbolic efficiency only contributes slightly to the overall tolerance to alcohol
Most alcohol tolerance is functional
o Alcohol has an effect on nearly every tissue in the body
Alcohol is small
alcohol is readily soluble in both fats and water
o Hypothermia: Decrease in body temperature
Alcohol increases dilation of the blood vessels near the surface of the skin
Dilation of surface vessels increases the amount of heat lost to the air from the body
Due to this loss, the body's temperature drops during alcohol consumption
o Diuretic: Increases the production of urine by the kidneys
o Hangover: Next-day withdrawal syndrome of alcohol; Symptoms include

 Headache
Nausea
Vomitting
Tremulousness
o Chronic alcohol abuse is associated with severe withdrawal, which occurs in 3 phases
Phase 1:
Begins 5-6 hours after the lst drink
Symptoms include
o Tremors
o Nausea
o Sweating
o Vomiting
o Agitation
o Headache
o Abdominal Cramps
o Occasionally accompanied by hallucinations
Phase 2:
Begins 15-30 hours after last drink
Characterized by convulsive activity
Convulsions during stage 2 can be lethal
Phase 3:
Begins 24-48 hours after last drink
Characterized by onset of Delerium Tremens
Delerium Tremens (DTs): The phase of alcohol withdrawal syndrome characterized by
o Hallucinations
o Delusions
o Agitation
o Confusion
o Hyperthermia
o Tachycardia.
o Hyperthermia: High body temperature
o Tachycardia: Rapid heart beat
o Delerium Tremens can be fatal
o Chronic alcohol consumption causes profuse brain damage
Korsakoff's Syndrome: A neuropsychological disorder that is common in alcoholics and
whose primary symptom is memory loss.
Caused by a deficiency in thiamine
Alcohol indirectly causes Korsakoff's syndrome
Alcohol consumption also causes brain damage indirectly by increasing the likelihood of
stroke
Alcohol reduces the flow of calcium into neurons by affecting the cells ion channels
Disrupts normal functioning of secondary messengers within cells
Disrupts GABAergic and glutaminergenic transmission
Triggers apoptosis (cell death)
o Cirrhosis: Scarring, typically of the liver.

 Major cause of death among heavy alcohol users

o Alcohol increases the likelihood of heart attack
Alcohol erodes the muscles of the heart
o Increases susceptibility to oral and liver cancer, stomach ulcers, pancreatitus, gastritus
Increases susceptibility by irritating the lining of the stomach and digestive tract
Pancreatitus: Inflammation of the pancreas
Gastritus: Inflammation of the stomach
o 1-2 drinks per day is associated with increased risk of
Breast cancer
Prostate cancer
Ovarian cancer
Skin cancer
o Fetal Alcohol Syndrome (FAS): A syndrome produced by prenatal exposure to to alcohol and
characterized by
Brain damage
Mental retardation
Poor coordination
Poor muscle tone
Low birth weight
Retarded growth and/or physical deformity
Affects children whose mothers were heavy drinkers during pregnancy
There is no time during pregnancy that consumption of any level of alcohol is safe
There is no level of alcohol that is safe for pregnant women to consume without effects of
the baby
Full FAS is rare in children of mothers who consumed 1-2 drinks per day during
pregnancy
Children born to these mothers often had cognitive deficits even though they were no
disgnosed with FAS
o No current cure for alcoholism
o Disulfiram: A drug that blocks the normal metabolism of alcohol and has been used in the
treatment of alcoholism
Produces the accumulation of acetaldehyde in the bloodstream
Acetaldehyde: One of alcohol's breakdown products
High levels of acetaldehyde produce symptoms of
o Flushing
o Dizziness
o Headache
o Vomiting
o Difficulty breathing
Only useful in hospitalization or out patient environments where the patient takes the
medication each day und supevision
O Marijuana
o Cannabis Sativa: The common hemp plant which is the source of marijuana.
o Joint: Cigarette made of marijuana
Most common method of consuming cannabis

o THC: Delta 9 Tetrahydrocannibinol, the main psychoactive constituent of marijuana

Primary psychoactive component of cannabis
Over 80 other cannabinoids present in cannabis plants
o Cannabinoids: Psychoactive ingredients within the cannabis plant that resemble the body's
endogenous cannabinoids (ie. Anandamide)
Smoked cannabis contains over 80 unique cannabinoids other than THC
o Hashish: Dark, corklike material extracted from the resin of the leaves and flowers of cannibus
sativa.
o Hash Oil: Potent form of cannabis distilled or processed fro hashish
o Marijuana: Name for cannabis introduced to the southern United States around the 20th
century
o Cannabis bears no resemblance to opiate narcotics
o Effects of cannabis at social doses are difficult to identify and measure and greatly influenced
by social situation
"To an unknowing observer, an individual in this state of consciousness would not appear
noticeably different" (National Commission on Marijuana and Drug Abuse, 1972)
o High doses cause a variety of temporary impairments
Short-term and long-term memory formation for events occurring while high
Memory retrieval (Hippocampus, an area of the brain rich in cannabinoid receptors is
responsible for both memory formation and memory retrieval)
Interferes with the performance of tasks that require multiple steps in order to complete
Speech may become slurred
Meaningful conversation may become difficult
Sense of unreality is common
Emotional intensification
Sensory distortion
Feelings of paranoia
Motor impairment
o Addiction potential for cannabis is low
Only 10% of users use cannabis daily
Obvious withdrawal signs are rare (exception being contrived laboratory experiments in
which the administered dose is extraordinarily high)
o Long-term use of cannabis is much less harmful than the long-term use of alcohol and tobacco.
o Narcotic: A legal category of drugs, mostly including opiates.
o Anandamide: The first endogenous endocannabinoid to be discovered and characterized.
o Adverse effects of long-term use of cannabis include
Heightened sensitivity to illnesses of the respiratory system (If cannabis is administered
through smoking - alternative methods of administration include oral ingestion and
vaporization, which delivers cannabinoids to the respiratory tract but not tar or other
harmful carcinogens)
Individuals susceptible to heart attack are at risk from single, large doses, particularly if they
have situational tolerance and are in an unfamiliar setting
There is no evidence that suggests longterm use of cannabis is related to brain damage
No evidence that cannabis leads to long-term memory loss
There is a potential link between cannabis use and schizophrenia, but no causal link has
been demonstrated.

 Individuals with a history of schizophrenia in their families should avoid use of cannabis
o Variety of medicinal uses for cannabis have been brought to the attention of the medical
community
Treats nausea
particularly effective in cancer patients who are unresponsive to other treatments
Increases appetite
Particularly effective in AIDS patients
Prevents seizures
Dilates bronchioles of asthmatics
Decreases severity of glaucoma
Reduces some forms of pain
Medicinal use of THC does not appear to be associated with any adverse side effects
o Discovery of receptors for THC in the brain changed research on cannabis permanently
Two receptors are CB1 and CB2
CB1 found to be the most prevalent receptors in the brain
CB2 found in the brain stem and cells of the immune system
Receptors in the brain are for endocannabinoids like anandamide
O Cocaine and other Stimulants
o Stimulants: Drugs that produce general increases in neural and behavioural activity.
o Cocaine: A potent catelcholamine agonist and stimulant that is highly addictive.
Cocaine and derivatives are commonly abused
Prepared from the leaves of a coca bush (Grown in Bolivia and Peru)
Coca Paste: Crude extract made directly from the leaves of the coca plant
o Ingestible form of cocaine
Cocaine Hydrochloride: Refined white powder that is extracted from treated coca
paste
o Most research has focused on cocaine hydrochloride
o Snortable form of cocaine
o Effective as a local anesthetic
Crack: A potent, cheap, smokable form of cocaine
o Made by boiling cocaine hydrochloride in a baking soda and water solution until the
water has evaporated
o Crack is impure and difficult to dose because it is consumed by smoking
o Difficult to research
Cocaine is highly effective as a local anesthetic
Prescribed as an anesthetic until lidocaine and procaine became available
Lidocaine and procaine are derivatives of cocaine
o Lidocaine is also used in reversible lesion studies
Non-medicinal psychoactive symptoms include
Wave of well-being
Feelings of self-confidence
Alertness
Energization
Friendliness
Outgoing and talkative

o
o

Fidgety
Less than usual desire for food and sleep
Tolerance develops to many of cocaine's effects such as the rush of euphoria
Sensitization is seen to convulsive and sensorimotor effects
Ie. Taking more of the drug increases convulsions instead of reducing them.
Highly addictive
Withdrawal is relatively mild
Bad mood swing
Temporary insomnia
Cocaine Sprees: Binges of extremely high cocaine use lasting for approximately a day or two
Spree typically ends when the cocaine is gone or the user begins to experience serious toxic
effects
May result in cocaine psychosis
Cocaine Psychosis: Psychotic behaviour observed during a cocaine spree, sometimes
resembling paranoid schitzophrenia
Paranoid Schizophrenia:
During cocaine sprees, individuals are at risk of
Losing consciousness
Seizures
Respiratory arrest
Heart attack
Stroke
Cocaine and its derivatives work by blocking dopamine transporters
Dopamine Transporters: Molecules in the presynaptic membrane of dopaminergenic
neurons that attract dopamine molecules in the synaptic cleft and deposits them back
inside the neuron.
Amphetamine: A stimulant drug whose effects are similar to cocaine
Also called "speed"
Can produce amphetamine psychosis similar to cocaine
D-Amphetamine: Dextroamphetamine, the most commonly consumed form from 1960's to
1990's
Consumed orally
Amphetamine Psychosis: syndrome of psychotic symptoms resulting from amphetamine
sprees.
Similar in symptomology to cocaine psychosis
Methamphetamine: More potent form of amphetamine than D-amphetamine
Overtook D-amphetamine in popularity in the 1990's
Commonly referred to as "Meth"
Crystallized form is more potent form
Smokeable
Most commonly used amphetamine today
MDMA: Also known as "ecstasy"
Form of amphetamine
Taken orally
Impairs dopaminergic and seratonergic action in animals

Effect of ecstasy on humans is less clear

Taking ecstasy causes several temporary impairments
Executive function
Decision making
Inhibitory self control
Cortex and limbic disfunction shown on fMRI scans
Amphetamines and other stimulants create their effect by increasing the number of
monoamines released into the synapse
Long term use of stimulants has a negative impact on brain health and performance
Deficits measures of seratonergic and dopaminergic function
Abnormalities of the cortex and limbic system during executive decision-making tasks
and tasks requiring self-inhibition
Individuals who have used methamphetamine for an average of 10 years show distinct
decreases in the volume of various parts of the brain as compared to controls who have
never used methamphetamine
Experiments on non-human subjects have confirmed the deleterious effects of
atimulants on the brain
Cardiovascular and electroencephalographic abnormalities have been found in
methamphetamine addicts
Stimulants are teratogens which can cause
o Behavioural abnormalities
o Neurological abnormalities
o Cardiovascular problems
O Opiates: Heroine and Morphine
o Opium: The sap that exudes from the seed pod of the opium poppy.
o Morphine: The major psychoactive ingredient in morphine.
Obtained from the sap of the opium poppy
o Codeine: A relatively weak psychoactive ingredient of opium.
Obtained from the sap of the opium poppy
o Opiates: Morphine, codeine, heroin, and other chemicals with similar structures and effects.
Generate their effects by binding to receptors for endogenous opiates
o Endorphins: A class of endogenous opioids.
o Enkephalins: The first class of endogenous opioids to be discovered.
o Opiates have medicinal uses
Highly effective as an analgesic
Analgesic: Drugs that reduce pain.
Used to reduce cough
Used to treat diarrhea
o Carry a high risk of addiction
o 3 Events occurred in history that deepened the impact of opioid addiction
1644 the emperor of China banned tobacco smoking
this ban caused gradual increases in opium smoking
Opium smoking was also make more popular by the British East India Trading company
smuggling opium into China
Smoking opium has a greater effect than ingesting it

o
o
o
o

Many more people became addicted to opium

1803 The main psychoactive ingredient of opium - morphine - was isolated
Became commercially available in the 1930's
1856 The hypodermic needle was invented
Injured were introduced to morphine through a needle
Until early in the 20th century, opium was legally available in most places of the world
Opium was an ingredient in common cakes, candies, wines and medicinal brews
Laudanum: Popular mix of opium and alcohol
Carminitive: Drug which expels gas from the digestive tract, reducing stomach cramps and
flatulence
Pure morphine required a prescription from a doctor
Doctors prescribed morphine for so many common ailments
Many individuals who could afford a doctor also had opiate addictions
Harrison's Narcotic Act: The act, past in 1914, that made it illegal to sell or use opium,
morphine, or cocaine in the United States
Continued to be legally prescribed for its analgesic properties
Did not include the semi-synthetic heroin at the time of passing
Addiction is fuelled by the intense rush that follows injection of opiates
Tolerance and physical dependence quickly develop
Desire to avoid withdrawal effects promotes further usage
Though opiates are highly addictive and opiate withdrawal can be very uncomfortable, the
risks associated with long-term use of opiates is very low
Many health hazards relating to use of opioids are related to the use of needles rather than
the effect of the drug
Severity of withdrawal for most doses has been exaggerated
Heroin: A powerful semisynthetic opioid
Synthesized by adding two acetyl molecules to morphine
Two extra molecules allow heroin to cross the blood-brain barrier more readily
Make Ted in 1898 by Bayer drug company as a superior form of advil
Since opioid addicts were unable to use codeine and morphine, they turned to the much
more potent heroin
Heroin was made illegal to possess, buy or sell in 1924
Heroin addicts seek the pleasurable rush following injection of heroin
Intense abdominal orgasmic pleasure
Evolves from pleasure into drowsy euphoria
Heroin addiction has been attempted to be treated with methadone
Methadone binds to opiate receptors and releaves withdrawal symptoms without
producing an intense rush of pleasure
Administered orally
Buprenorphine has also been used to treat heroin addiction
Similar to methadone, but lasts longer in the body
Idea behind methadone and buprenorphine addiction therapy is to replace the drug of
addiction with a less addictive substitute.
Classic opiate withdrawal typically begins 6 to 12 hours after the last dose
First signs include fidgitiness, restlessnes, watery eyes, running nose, sweating and

yawning
Often the addict falls into fitful sleep
Extreme cases are accompanied by chills, shivering, profuse sweating, gooseflesh,
nausea, vomiting, diarrhea, cramps, dilated pupils, tremor, muscle pain, muscle cramp
Even in its most severe form, opiate withdrawal is not as terrifying or detrimental to the
body as alcohol or barbituate withdrawal
Extended exposure to opiates carries surprisingly little risk
Constipation
Pupil constriction
Menstrual irregularity
Reduced libido
Most medical risks associated with long-term opiate use are not directly associated with the
drug itself
Many health hazards arise out of the tension caused between the addictive power of
opiates and how governments attempt to eradicate addiction by making the drug illegal
Most addicts must purchase their supply from illegal dealers at highly inflated prices,
forcing them to live in a hsbitual cycle of crime and poverty in order to support their
habit unless they are wealthy
Individuals in this situation are often poor, undernourished, I'll cared for and may or
may not have to turn to prostitution
Run the risk of contracting AIDS and other infections from unsafe sex and unsterile
needles
Never know for sure what they are injecting since street heroin is often cut (stretched
with a similar looking substance in order to sell more from the same amount of
substance)
death due to heroin overdose is widely misunderstood
Blood levels of heroin are often low while blood levels of other CNS depressants are
high, indicating that what is often termed heroin overdose is a case of drug interaction
Some deaths from heroin overdose are a consequence of its legal status. When heroin
has been cut with a lethal substance or a particularly pure shipment causes far more
effect than the individual is prepared for
Most people attribute the increase in deaths due to opiate overdose to increases in heroin
use, but almost all increases in overdose death are attributable to prescription narcotics
Swiss government took an alternative approach to heroin addiction
Funded hospitals where, for a small fee, heroin addicts can receive clean heroin injected
by a physician.
Research indicates that this solution has had a tremendously positive effect on the
country's social health
o Most addicts gave up their criminal lifestyles and improved their health
o Addicts were able to return to their homes and families
o Crime and addiction no longer evident on Swiss streets
o Rates of new heroin addicts is dropping
Heroin addiction is viewed as less cool when it is treated as a legitimate illness
o Safe injection sites reduce the spread of illness due to unsterile needles
o Safe injection sites reduce death due to overdose
Comparison of the Hazards of Tobacco, Alcohol, Marijuana, Cocaine and Heroin

o Alcohol and tobacco are associated with the greatest negative health risks in our society
o Tobacco has been implicated in the most deaths per year
Alcohol is second
15.4: Biophysiological Approaches to Theories of Addiction
O Question of do we need it or do we want it is the same question that has been asked in research on
eating sleeping and sexual behaviour as well
O Physical Dependence and Positive Incentive Perspectives of Addiction
o Physical-Dependence Theories of Addiction: Theories holding that the main factor that
motivates drug addicts to keep taking drugs is the prevention or termination of withdrawal
symptoms.
o Earliest theory explaining addiction
o Methods of treating addiction were originally based on the physical dependence view of
addiction
Patients were gradually detoxified from the substance and then released
Detoxified Addicts: Addicts who have none of the the drug to which they are addicted to in
their body and are not experiencing withdrawal syndrome.
Detoxified addicts often returned to their drug-abusing behavioural patterns
o Failure of detoxification therapy to curb addiction makes sense for two reasons
Many highly addictive drugs such as cocaine and smphetsmines do not cause harsh or
intolerable withdrawal symptoms
Pattern of drug taking in regular users typically follows a binge and purge type cycle for a
variety of reasons
Weekend sprees may be most compatible with the addict's work schedule
May not have the money to continuously binge
Binges may land individuals in jail, forcing them to be without for a number of days
Some repeatedly try to give up the drug without success
o Positive Incentive Theories: Theories holding that the primary factor in most cases of drug
addiction is a craving for the pleasure-producing properties of the drug.
o Hedonic Value: The amount of pleasure produced by an action.
O From Pleasure to Compulsion: Incentive Sensitization Theory
o Positive-Incentive Value: The anticipated pleasure associated with a particular action such as
taking a drug.
o Hedonic Value: The amount of pleasure produced by an action.
o Incentive Sensitization Theory: Theory that addictions develop when drug use sensitizes the
neural circuit mediating wanting of a drug, not necessarily likingn for the drug.
With drug use, positive incentive value increases as memory of the drug's effects are
solidified in the individual's mind.
As the individual continues using the drug, however, the hedonic value decreases due to
drug tolerance.
As positive incentive value continues to increase and hedonic value continues to decrease,
the addict desires the drug more, but experiences fewer of its effects.
Addicts often report craving the drug's pleasurable effects but finding that the effects are not
what they used to be
O Relapse and Its Causes
o Biggest problem is not getting addicts to stop taking the drug, biggest problem is to keep them

abstinent
o Relapse: To return to a diseased state after a period of temporary improvement. For example,
returning to an addictive substance after a period of voluntary abstinence.
Three fundamentally different kinds of relapse have been identified
Drugs are often used as stress relievers
o Situations of great stress on he individual can lead to relapse
o Sharp increase in tobacco and liquor sales after the 9/11 terrorist attacks
Priming: When a single exposure to the drug causes a full relapse into drug-addiction
behaviour
After a period of abstinence, individual feels they have their addiction under control and
samples their previously used substance
This sampling puts the addict back into the cycle of addiction
Conditioned withdrawal syndrome can cause relapse by creating cravings and conditional
compensatory responses even though the drug has completely left the individual's system
Returning to a location where the drug was previously used
Thinking about situations in which the drug was previously used
Performing behaviours that were previously associated with drug use
Many US soldiers who are addicted to heroin in the battlefield come back home and are
able to shake theirnopioid addiction
15.5: Intracranial Self-Stimulation and the Pleasure Centers of the Brain
o Brain circuitry exists that reinforces behavior by making it feel rewarding
o Intracranial Self-Stimulation (ICSS): The repeated performance of a response that delivers
electrical stimulation to certain areas in animal's brain.
O Fundamental Characteristics of Intracranial Self-Stimulation
o Pleasure Centers:
Many species will work for an electrical reward to their brain's pleasure center
Discovered by Old and Milner
Hypothesized that drug use may be reinforced by activating one or more of these centers
Self-stimulation response time for septal or lateral hypothalamic stimulation is so high
animals often only stop from exhaustion
o When the current is turned off, animals almost immediately stop self-stimulating
o When an animal who has already had an experience with self-stimulation is removed for a time
and then put back in the same situation, they must be primed before they will press the lever at
the original high rate
o Stimulation of the pleasure centers in the presence of food or water will often precipitate eating
and drinking
o Producing natural increases in motivation increases rates of self-stimulation
O Mesotelencephalic Dopamine System and Intracranial Self-Stimulation
o Plays an important role in studies of ICSS
o Neurons project from two midbrain areas to the telencephalon
Cell bodies are located within two midbrain nuclei
Substantia Nigra
Ventral Tegental Area
o Mesotelencephalic Dopamine System: The ascending projections of the dopamine-releasing
neurons from the substantial nigra and ventral tegmental area of the mesencephalon into various

regions of the telencephalon.

o Two major patheays in the mesotelencephalic dopamine system
Some intermingling of neurons between the pathways
Nigrostriatal Pathway: The pathway along which axons from the substantia nigra project
to the striatum.
Substantial nigra neurons project to dorsal striatum
Substantia Nigra: The midbrain nucleus whose neurons project via the nigrostratiatal
pathway to the striatum of the basal ganglia; it is part of the mesotelecephalic dopamine
system and degenerates in cases of Parkinson's disease.
Degenerates in patients with Parkinson's disease
Mesocorticolimbic pathway:
Neurons from the Ventral tegmental neurons project to cortical and limbic sites,
including the nucleus accumbens. Areas neurons project to include
o Septum
o Amygdala
o Olfactory Tubule
o Nucleus Accumbens
o Prefrontal Neocortex
o Limbic Cortex
Ventral Tegmental Area: The midbrain nucleus of the mesotelencephalic dopamine
system that is a major source of the mesocorticolimbic pathway.
Nucleus Accumbens: Nucleus of the ventral striatum and a major terminal of the
mesocortical limbic dopamine pathway.
o Major reward center of the brain
o Integral component of the ICSS reward pathway
o Related to natural rewarding feelings such as the feeling we get when we eat or
make love
o Associated with addictive properties of some psychoactive substances
Self stimulation sites that do not have dopaminergic neurons project here
o Increase in dopaminergic release seen in this pathway during self-stimulation studies
Dopamine agonists that affect the mesocorticolimbic pathway tend to decrease selfstimulation in laboratory animals
o Dopamine antgonists generally tend to increase self-stimulation in laboratory
animals
Lesions to this pathway disrupt self-stimulation
Many of the brain sites at which ICSS occurs are part of the mesocorticolimbic pathway
15.6: Early Studies of Brain Mechanisms of Addiction: Dopamine
o Neural addiction curcuitry could not have evolved to mediate drug use
Most chronic drug use is not adaptive
o Understanding neural basis of drug addiction lies in neural basis for motivation and how it is
influenced by psychoactive substances
O Two Key Methods for Measuring Drug-Produced Reinforcement in Laboratory Animals
o Drug Self-Administration Paradigm: A test of the addictive potential of a drug in which
laboratory animals can inject the drug into themselves by pressing a lever.
The more often the animal self-administers the substance, the more addictive it is

considered
Cannula is surgically implanted into the animal's brain
Cannula: Fine, hollow tube that is implanted in the body for the purpose of injecting or
extracting fluids.
Animals allowed to freely self-inject substances to which humans become addicted to often
demonstrates that animals follow similar reaction patterns to people
o Conditioned Place-Preference Paradigm: A test that assesses a laboratory animal's preference
for environments in which it has previously experienced drug effects.
Animals offered more addictive substances will prefer to spend more time in the room
where they are administered the psychoactive substance
Mouse or rat repeatedly receives a dose of the substance being studied in the same
compartment
After the animal has been detoxified from the effects of the substance it is placed the box
with the drug and non-drug compartment
The animal's preference for the drug compartment is measured to determine level of
addiction potential
Drug Compartment: One compartment of a two compartment cage; Compartment where
the animal receives dosages of the studied substance;
Control Compartment: One compartment of a two-compartment cage; Compartment
where the animal does not receive administrations of psychoactive substances.
Benefit of the conditioned place preference paradigm is that since animals are tested when
they are detoxified, the test measures pleasure incentive without the confounding effects
that can be caused by the intoxicating effects of the substance being studied
Early Evidence of the Involvement of Dopamine in Drug Addiction
o Dopamine's role in mediating addiction is suggested by the results of self-stimulation studies
o Dopamine antagonists interfere with self-stimulation
o Dopamine antagonists reduce cravings and pleasurable feelings associated with eating food
o Nucleus Accumbens plays an important role in the dopamine reward system
The Nucleus Accumbens and Drug Addiction
o Animals self-administer microdoses of addictive substances directly into the nucleus
accumbens
These microinjections lad to strongly conditioned place preference
Lesions to the nucleus accumbens or to the ventral tegmental area interferes with self
stimulation and conditioned place preference associated with microinjections
o Both addictive drugs and natural reinforcement results in increased dopamine in the nucleus
accumbens
o Dopaminergic pathways to the nucleus accumbens from the ventral tegmental area proved to be
particularly associated with subjective feelings of pleasure and reward
Support for the Involvement of Dopamine in Addiction: Evidence from Imaging Human Brains
o PET displacement studies
Dopamine increases in the nucleus accumbens when addictive drugs are administered
Dopamine increase correlated to subjective high reported by participants using the
substance in the study
o Overall dopamine function is decreased in participants with substance addiction
Dopamine levels return to normal during drug use and with the presence of conditioned
tolerance stimuli
Dopamine Release in the Nucleus Accumbens: What is its Function?

o Role of dopamine release in the nucleus accumbens is well documented as being related to the
reinforcement of drug seeking behaviour, natural rewards such as food and pleasurable brain
stimulation
o Ventral tegmental neurons (These neurons release their dopamine vesicles into the the nucleus
accumbens) fire at a rate proportional to the anticipated reward value of a stimulus
o Some studies indicate that the nucleus accumbens is more related to the anticipated reward than
the experience of reward itself
Emerging hypothesis is that dopamine release in the nucleus accumbens normally signals
the difference between expected and experienced feelings of reward
Cell bodies in the ventral tegmental area fire at a rate equivalent to anticipated reward
When the reward presented was the same, no change in firing occurred
Greater rewards than expected produced greater levels of firing and less reward than
expected produced decreased levels of firing
15.7: Current Approaches to Brain Mechanisms of Addiction
O Current approaches to brain mechanisms take into account years of drug and addiction research
O Current Issues in Addiction Research
o Addiction is Psychologically Complex
Addicted patients are different from healthy controls on a number of psychologically
relevant factors that may contribute to the development of addiction
Drug addicts have been found to differ from healthy controls in the following ways
Poorer decision making skills
Engaging in excessive risk taking
Deficits in self-control
Efforts to treat addiction must address these psychological factors in order for the program
to be successful
o Addiction is a Disturbance in Decision Making
Addicts display poor decision making skills which suggests prefrontal cortex impairment
Primary symptom of drug addiction is a deficit in decision making
Initiated inclusion of research from other fields related to decision making into drug
research
Initiated inclusion of research on drug abuse into research regarding decision making
o Addiction is Not Limited to Drugs
Addiction is also related to chronic eating, sexual behaviour, shopping, stealing etc...
Important symptom is being unable to stop a behaviour despite its negative influence on
one's life
Many behaviours fall into this category, taking drugs is only one of those behaviours
o Addiction Involves Many Neurotransmitters
Glutamate
Endogenous Opioids
Norepinephrine
GABA
Endocannabinoids
Brain Structures That Mediate Addiction: The Current View
o 3 Stages of addiction
Initial Drug Taking

Involvement of mesocorticolimbic pathway

o Nucleus accumbens
Prefrontal Lobes acts when making the initial decision to take the drug
Hippocampus are assumed to provide relevant background information and previous
experiences related to the drug
Amygdala coordinates positive and negative emotions related to substance use
Change to Craving and Compulsive Drug Taking
Dorsal Striatum
o Change in how the dorsal striatum reacts to substances
o Change in reaction to substance-related cues
o As use of the substance continues, control is gradually transferred from the nucleus
accumbens (pleasure center) to the dorsal striatum (habit formation center)
Hypothalamic stress circuits begin to act in conjunction with the dorsal striatum
Influence of the prefrontwl cortex in making decisions related to the substance declines
Relapse
Each type of relapse is mediated by differing brain structures interacting with the dorsal
striatum
Priming doses - prefrontal cortex
Drug-associated cues - amygdala
Stress - Hypothalamic Stress Circuits

15.8: A Noteworthy Case of Addiction

O Sigmund Freud
o Heard about its use in soldiers to help them make difficult maneuvers
Freud became intrigued and acquired some for himself
Gave cocaine to his coworkers, friends and family, even mailed some of the drug to his
fiancee
o Famous essay "Song of Praise" was written by Freud and published in 1884
Stimulated interest in the use of cocaine
Critical reaction to Freud's premature support of the drug
Evidence accumulated that cocaine is highlynaddictive and can cause psychosis at high
levels
Criticism against Freud also mounted
o After 3 years, Freud stopped using Cocaine
Despite years of cocaine use, Freud had no apparent difficultynstoppingnhis cocaine habit
o 7 years later, his physician ordered him to stop smoking due to a heart condition
o Even though Freud had no trouble stopping his cocaine habit, he found it impossible to quit
smoking.
Developed cancerous sores on the inside of his mouth due to smoking and still could not
stop
Began to experience severe heart pain but was still unable to quit smoking
Hospitalized for his heart condition some time later and quit smoking
Health improved immediately following cessation of smoking
Began smoking 23 days after quitting
Had 33 operations to contend with his oral cancer and still could not quit smoking

o Freud died of Cancer in 1939