Drug Use, Drug Addiction,
and the Brain’s
Reward Circuits
Dugos, Marianne Pearl
Molina, Marianne Grace
Robles, Francisca Mae
Chapter
Overview
01
Basic Principles of Drug Action
02
Role of Learning in Drug
Tolerance
03
Five Commonly Used
Drugs
04
Comparing the Health Hazards of Commonly
Used Drugs
05
Early Biopsychological Research on
Addiction
06
Current Approaches to the Mechanisms
of Addiction
Basic
Principle
s of Drug
Action
Drug Administration, Absorption, and
Penetration
of
the
CNS
Oral ingestion
01
2 main advantages: ease and safe
Injection
02
03
Effects of injected drugs are strong, fast, and predictable
Drug injections typically done through:
(SC) subcutaneously – into fatty tissue just beneath the
skin
(IM) intramuscularly – into large muscles
(IV) intravenously – directly into veins at points where they
run just beneath the skin
Inhilation
Difficult to regulate the dose of inhaled drugs
04
Absorption through mucous membranes
Nose, mouth, and rectum
Drug Action, Metabolism, and
Elimination
Drug
Penetration of
the CNS
Blood-brain barrier
(protective filter)
makes it difficult for
dangerous
bloodborne
chemicals to get into
the extracellular
space of CNS
neurons and glia.
Mechanisms of
Drug Action
Psychoactive drugs
influence the
nervous system in
many ways
Act diffusely on
neural membranes
throughout the
CNS
Others act in a more
specific way:
By binding to particular
synaptic receptors
By influencing the synthesis
Transport
Release
Deactivation of particular
neurotransmitters
Influencing the chain of
chemical reactions elicited in
postsynaptic neurons by the
activation of their receptors
Drug Metabolism
and Elimination
The actions of
most drugs are
terminated by
enzymes
synthesized by the
liver.
Drug metabolism –
conversion of
active drugs to
nonactive forms.
Drug Tolerance
A state of decreased
sensitivity to a drug that
develops as a result of
exposure to it
Demonstrated in 2 ways:
By showing that a
given dose of drug has less
effect than it had before
exposure
By showing that it
takes more of the drug to
produce the same effect
Drug tolerance is a shift in
the does-response curve to
the right
Drug Tolerance,
Drug Withdrawal
Effects, and
Physical
Three important points to remember
about the
specificity of drug
Dependence
tolerance:
Cross tolerance – one drug can
produce tolerance to other drugs that
act by the same mechanism
Drug tolerance often develops to some
effects of a drug but not to others.
Drug sensitization – increasing
sensitivity to a drug.
Drug tolerance is not a unitary
phenomenon; that is, there is no single
mechanism that underlies all examples
of it.
Two categories of
changes underlie drug
tolerance:
Metabolic – drug tolerance
that results from changes
that reduce the amount of
the drug getting to its sites
of action
Functional – dug tolerance
that results from changes
that reduce the reactivity of
the sites of action to the
drug.
Drug
Addiction:
What is it?
Drug-addicted
individuals are
habitual drug users,
but not all drug users
are drug-addicted
individuals.
Drug-addicted individuals –
habitual drug users who continue
to use a drug despite its adverse
effects on their health and social
life, and despite their repeated
efforts to stop it.
Sometimes take drugs to
prevent or alleviate their
withdrawal symptoms
Role of Learning in
Drug Tolerance
An important line of psychopharmacologic
study research has shown that learning
plays a major role in drug tolerance.
Research on the role of drug tolerance has
focused on two phenomena:
Contingent Drug Tolerance
Conditioned Drug Tolerance
Contingent Drug Tolerance
Contingent drug tolerance refers to
demonstrations that tolerance develops only to
drug effects that are actually experienced.
This Drug tolerance is contingent or dependent on
the repeated expression of the drug effect rather
than on mere exposure to the drug.
Before-and-after design
- In before-and-after experiments, two
groups of subjects receive the same
series of drug injections and the same
series of repeated tests, but the
subjects in one group receive the drug
before each test of the series and
those in the other group receive the
drug after each test of the series. At
the end of the experiment, all subjects
receive the same dose of the drug
followed by a final test so that the
degree to which the drug disrupts test
performance in the two groups can be
compared.
Conditioned Drug
Tolerance
Conditioned Compensatory
Responses
Studies of conditioned drug
tolerance focus on the
situations in which drugs
are taken.
A conditioned compensatory response is
an automatic response that the body
and mind experience that is opposite
of the effects of alcohol or drugs.
Reinforcement
exercises
Conditioned drug tolerance refers to demonstrations that
tolerance effects are maximally expressed only when a
drug is administered in the same situation in which it has
previously been administered.
Most demonstrations of
conditioned drug tolerance
have employed:
Exteroceptive
.
stimuli
- (external,
public stimuli,
such as the
drugadministration
environment) as
the conditional
stimuli.
Interoceptive
stimuli
- (internal,
private
stimuli) are
just as
effective in
this role.
Five
Commonl
y Used
Drugs
Tobacco
Nicotine – major psychoactive
ingredient of tobacco—and some
4,000 other chemicals collectively
referred to as tar, are absorbed
through the lungs.
Drug craving – effective
state in which there is a
strong desire for the drug.
Habitual smokers who stop smoking experience
a variety of withdrawal effects:
Depression
Anxiety
Restlessness
Irritability
Constipation
Difficulties in sleeping and concentrating
Smoker’s
Characterized
by chest
syndrome
pain, labored breathing,
wheezing, coughing, and
heightened susceptibility
to infections of the
respiratory tract.
Buerger’s
Disease
The blood vessels
especially those
supplying the legs,
become constricted.
Teratogen
An agent that can
disturb the normal
development of the
fetus.
Alcohol
Is a depressant (reduce arousal and stimulation) because at moderateto-high doses it depresses neural firing; however, at low doses, it can
stimulate neural firing and facilitate social interaction
Moderate doses can cause the alcohol drinker to lose control which
can lead to socially unacceptable actions
High doses result in unconsciousness; and if blood levels reach 0.5
percent, there is a risk of death from respiratory depression
Hangover – withdrawal from alcohol
Four phases:
After 6-8 hours – anxiety, tremor, nausea, and tachycardia (rapid heartbeat)
After 10-30 hours – hyperactivity, insomnia, and hallucinations
Between 12 and 48 hours – convulsive activity
After 3-5 days and lasts after a week – delirium tremens (DTs) which are characterized by
disturbing hallucinations, bizarre delusions, disorientation, agitation, confusion,
hyperthermia (high body temperature), and tachycardia.
Korsakoff’s syndrome
A neuropsychological disorder characterized
by memory loss, sensory and motor
dysfunction, and, in its advanced stages,
severe dementia
Cirrhosis
Extensive scarring of the liver
Fetal Alcohol Syndrome (FAS)
Condition that the offspring of mothers who
consume substantial quantities of alcohol
during pregnancy
Mariju
ana
Marijuana is the name commonly given to
the dried flower buds of Cannabis—the
common hemp plant if which there are three
species:
Cannabis sativa
Cannabis indica
Cannabis ruderalis
THC (delta-9-tetrahydrocannabinoids) – a
constituent in which the psychoactive effects
of marijuana are largely attributable.
At low, usual “social” doses, the intoxicated
individual may experience an increased
sense of well-being.
High does impair psychological functioning
Tolerance to marijuana develops during periods of sustained use
No damage that can reasonably be attributed to marijuana use has
been found in the brains of living or deceased marijuana users.
However, three lines of indirect correlational evidence have a bearing
on the question:
Brain-imaging studies have found that hippocampal volumes
tend to be slightly reduced in some heavy marijuana users. However,
such findings might be the result of preexisting differences between
users and nonusers.
Heavy marijuana users tend to have memory problems.
However, because it is not clear whether the memory deficits
persist after the cessation of marijuana use, it is not clear if they are
indicative of persistent brain damage.
Heavy marijuana users are slightly more likely to be
diagnosed with schizophrenia—especially if they began using
marijuana during adolescence.
Marijuana may actually have neuroprotective effects.
Therapeutic effect of THC
Suppress nausea and vomiting in cancer patients
Stimulate the appetite of patients with AIDS
Block seizures
Dilate the bronchioles of asthmatics
Decrease severity of glaucoma
Reduce anxiety
Cocaine and Other
Stimulants
Stimulants
Drugs whose primary
effect is to produce
general increases in
neural and behavioral
activity.
Cocaine
hydrochloride is an
effective local
anesthetic supplanted
by procaine and
lidocaine.
Consumed by
snorting or by
injection
Cocaine is prepared
from the leaves of
coca shrub. A crude
extract called coca
paste has been made
directly from the
leaves and eaten.
Crack
Potent, cheap,
smokable form of
cocaine
Cocaine sprees – binges in which extremely high
levels of intake are maintained for periods of a day or
two.
Effects of cocaine sprees
1
Sleeplessness.
2
Tremors
3
Nausea
4
Hyperthermia
5
Psychotic symptoms called cocaine
psychosis
Withdrawal effects triggered by abrupt
termination of a cocaine spree are
relatively mild:
mood swing
insomnia
Amphetamine and its relatives are
currently the most widely misused
stimulants.
Consumed orally in the potent form called
d-amphetamine (dextroamphetamine).
Can also produce a syndrome of psychosis
called amphetamine psychosis.
In the 1990s, d-amphetamine was supplanted as the favored
amphetamine-like drug by several more potent relatives.
Methamphetamine or “meth” is commonly used in its
even more potent, smokable, crystalline form (crystal
meth).
3,4-methylenedioxy-methamphetamine (MDMA, or
ecstasy), which is taken orally, is another potent
relative. It is also an empathogen.
Dopamine transporters - molecules in the presynaptic
membrane that normally remove dopamine from synapses and
transfer it back intro presynaptic neurons.
Other stimulants increase the release of monoamines into
synapses.
Do stimulants have long-term
adverse effects on the health of
habitual users?
There is some evidence that they do.
Many studies have reported cognitive impairments in both
methamphetamine and MDMA users, though the effects have often
been small or difficult to reproduce. In addition, methamphetamine
and amphetamine users, but not cocaine users, have greater risk of
developing Parkinson’s disease.
There is also evidence of Parkinson’s disease: many
cocaine-dependent, amphetamine-dependent, and
methamphetamine-dependent patients have bee found to have
electrocardiographic abnormalities.
There is evidence that stimulant-dependent individuals have
less gray matter in their prefrontal cortex. However, because the
results are correlational, one cannot rule out other explanations.
The Opioi
ds:
Heroin an
d
Morphine
Opium – the dried form of sap by the seedpods of the
opium poppy—has several psychoactive ingredients.
Most notable are morphine and codeine, its
weaker relative.
Morphine, codeine, and other drugs that have similar
structures or effects are commonly referred to as opioids
which exert their effects by binding to receptors whose
normal function is to bind to endogenous opioids.
Two classes of endogenous opioid neurotransmitters that
bind to such receptors:
Endorphins
Enkephalins
Opioids have Jekyll-and-Hyde character:
On their Dr. Jekyll side, the opioids are effective
as analgesic (painkillers); they are also extremely
effective in the treatment of cough and diarrhea.
The kindly Dr. Jekyll brings with him the evil Mr.
Hyde—the risk of addiction.
Three historic events fanned the flame of opioid addiction:
1644, the Emperor of China banned tobacco
smoking, and this contributed to a gradual
increase in opium smoking in China.
Morphine, the most potent constituent of opium,
was isolated in 1803.
Hypodermic needle was invented in 1856, and
soon the injured were introduced to morphine through
needle.
Harrison Narcotics Act, passed in 1914,
made it illegal to sell or use opium,
morphine, or cocaine in the United
States—although morphine and its
analogues are still legally prescribed for
their medicinal properties. However, the
act did not include the semisynthetic
opioid heroin.
Heroin was synthesized in 1870 which
greatly increased its ability to penetrate
the blood-brain barrier.
1898, heroin was marketed by the Bayer
Drug Company claimed that heroin is
not addictive
Withdrawal syndrome usually begins 6 to 12 hours after the last dose.
er
g,
First sign is typically an increase in restlessness; the opioid us
begins to pace and fidget. Watering eyes, runny nose, yawnin
and sweating are also common during early stages of opioid
withdrawal.
Then the person often falls into a fitful sleep, which typically
lasts for several hours.
sh,
d
Once they wake up, the original symptoms may be joined in
extreme cases by chills, shivering, profuse sweating, goosefle
nausea, vomiting, diarrhea, cramps, dilated pupils, tremor, an
muscle pains and spasms.
e
Symptoms of opioid withdrawal are typically most severe in th
second or third day after the last injection, and by the seventh
day they have all but disappeared.
Even in its most severe form, however, opioid withdrawal is no
Main direct risks are constipation, pupil constriction,
menstrual irregularity, and reduced sex drive.
Many opioid users have taken pure heroin and
morphine for years with no serious ill effects.
Dr. William Steward Halsted, one of the
founders of John Hopkins Medical School and one of
the most brilliant surgeons of his day known as the
“father of modern surgery.”
He was addicted to morphine and the only time
his habit caused him any trouble was when he was
attempting to reduce his dosage.
High doses of heroin kill by suppressing breathing
Heroin overdose is not well understood:
Medical examiners often attribute death to
heroin overdose without assessing blood
levels of heroin.
Technological analysis at autopsy often
reveals that this diagnosis is questionable.
Primary treatments for heroin addiction in most
countries are:
Methadone – shown to improve success
rate but its adverse effects are
problematic
Buprenorphine – has fewer side effects
but is considered less effective than
methadone
Comparing the
Health
Hazards of
Commonly
Used Drugs
Interpreting Studies of the Health
Hazards of Drugs
The previous module described the health hazards of five
commonly used drugs, some legal, some illegal. You probably
noticed a repeated disclaimer: Interpretation of the adverse
effects observed in drug users is almost always complicated by
the fact that the relevant research is correlational.
Comparison of the Hazards of
Tobacco, Alcohol, Marijuana, Cocaine,
and Heroin
Compare the direct health hazards of alcohol,
tobacco, marijuana, heroin, and cocaine.
Tobacco has been implicated in approximately 5 million
deaths per year; alcohol in approximately 2 million deaths
per year; and all other drugs combined in about 250,000
deaths per year.
Early
Biopsycholog
ical Research
on Addiction
Physical Dependence and Positive Incentive
Perspective of Addiction
.
PHYSICAL
DEPENDENCE:
Traps addicted
individuals in a
vicious circle of drug
taking and withdrawal
symptoms.
POSITIVE-INCENTIVE:
Most addicted individuals
take drugs not to escape
or to avoid the unpleasant
consequences of
withdrawal, but rather to
obtain the drugs’ positive
effects
Intracranial Self-Stimulation and the
Mesotelencephalic Dopamine System
INTRACRANIAL SELF-STIMULATION PARADIGM (ICSS)
Rats, humans, and many other species will administer brief bursts of
weak electrical stimulation to specific areas of their own brain.
Pleasure centers-is the brain site capable of mediating the
phenomenon.
MESOTELENCEPHALIC DOPAMINE SYSTEM: It is a system of
dopaminergic neurons that projects from mesencephalon to
telencephalon.
Includes the substantia nigra and ventral tegmental area projecting to
prefrontal cortex, limbic cortex, olfactory tubercle, amygdala, septum,
dorsal striatum and nucleus accumbens.
Nigrostriatal
pathway:
Axons of
dopaminergic
neurons from
substantia nigra
projecting to dorsal
striatum.
Degeneration
assoc. with
Parkinson's.
Mesocorticolimbic
pathway:
Axons of
dopaminergic
neurons that have
their cell bodies in
the ventral tegmental
area projecting to
various cortical and
limbic sites.
Currently considered
important.
4 reasons why Mesocorticolimbic pathways considered to
play important role in mediating ICSS.
1.
Many brain sites
where self-stim
occurs are part of the
pathway
3.
Dopamine agonists
tend to increase ICSS
and antagonists tend
to decrease it
2.
ICSS often associated
with increase in
dopamine release in
this pathway
4.
Lesions in the
pathways tend to
disrupt ICSS
Early Evidence of the
Involvement of Dopamine in
What are 2 methods to measure Drug Addiction
the rewarding effects of drugs?
1. Drug self-administration
paradigm
Non human animals
press lever to inject drugs
intravenously to
themselves through
implanted cannulas (thin
tubes).
2. Conditioned placepreference paradigm
Non human animals
repeatedly receive a drug in a
drug compartment of 2compartment box. Then,
during the test phase, the
drug free rat is placed in the
box, and the proportion of
time it spends in the drug
compartment, as opposed to
the equal sized but distinctive
control compartment,
measured.
Nucleus Accumbens and Drug Addiction
The role of nucleus accumbens in drug addiction
1
Laboratory animals tend to self-administered microinjections of
dictive drugs directly into the nucleus accubens.
ad
2
Microinjections of addictive drugs into the Nucleus Accumbens produced a con
ditioned place preference for the compartment in which they were administere
d.
3
Lesions to either the Nucleus Accumbens or ventral tegmental area blocked t
he self-administration of addictive drugs into general circulation or the develop
ment of drug associated conditioned place preferences.
4
Both the elf-administration of addictive drugs and experience of natural
re
inforcers were found to be associated with elevated levels of extracellular dop
amine in the Nucleus Accumbens.
Current
Approaches to
the Mechanisms
of Addiction
Three Stages of in the
development of an addiction
1
Initial Drug Intake
.
The well known factors in initial drug taking are price and availability of the drug,
peer pressure, and prior life experiences.
- Food restriction, social stress, environmental stress facilitate the acquisition of
drug self administration by rats.
- Environmental enrichment, social interaction, access to nondrug reinforcers all
protect against the acquisition of drug self administration.
Novelty seeking behaviour - a behavioral trait commonly associated with initial
drug taking in humans.
-Drugs are viewed as tools, or instrument to medicate, stay awake, relieve stress
and anxiety,pleasure and etc.
2
. Habitual Drug Taking
Anticipated pleasure of the drug causes addictions
Positive-Incentive Value, Hedonic Value and Incentive
Sensitization theory relates to Habitual drug taking.
- positive-incentive value: refers to the anticipated pleasure
association with action.
- hedonic value: refers to the amount of pleasure that is actually
experienced.
- Incentive sensitization theory, is able to explain why some
drug users become habitual users and others do not. It is also able
to explain the discrepancy between the hedonic value and the
positive incentive value of drug taking in addicted persons.
2
.
Drug Craving & Repeated Relapse
The 3 diff. causes of drug relapse in addicted
individuals
1. Stress
2. Drug priming (a single exposure to formerly
misused drugs). Reassured by abstaining for a
long time that they have it under control
3. Exposure cues: cues that have previously
been associated with drug taking
Incubation of drug craving- Time dependent
increase in cue-induced drug craving and
relapse
Current Concerns about the Drug
Self-Administration Paradigm
Two sets of findings that have challenged relevance of drug self-admin
studies
Unnatural Housing and Testing Conditions
- rats housed individually and tested in a barren test chamber where the
only rewarding thing they can do is press a lever for a drug injection.
-given access to enriched environment, provided with opportunity to
obtain nondrug reinforcers, or housed in large naturalistic environment,
they were much less likely to self-admininister drugs.
- question relevance of rat experiments to human
2. Excessive Focus on Stimulants
- studies of opioid self-admin studies have led to different conclusions
- mesocorticolimbic pathway lesions/dopamine antagonists disrupt
habitual cocain self-administration, they did not disrupt habitual heroin
self administration.
Thank you!