Transcript Psychopharmacology

Chapter 8 Opener
Frequency of drug use
• 2002 survey of illicit drug
use
• 19.5 million Americans 12
years old or older
– 8.3% of the population
• 71 million – tobacco
– About 30%
• 120 million – alcohol
– About 50%
– 16 million – heavily (7%)
• 200 years ago there were few regulations
on drugs. None at the federal level
• There were also fewer drugs
– Tobacco
– Alcohol
– Opium
Factors contributing to modern views on drugs.
• 1) Alcohol temperance movement
– Benjamin Rush founded (late 1700s, early 1800s)
• Advocated abstaining from hard liquor
• Okay to have moderate beer or wine consumption
– Rush pointed out physiological consequences of
alcohol use
– Also pointed out impairment of moral faculty
• Many still think of alcohol use negatively
– Also probably influenced peoples view of drug use
• Drug use = criminal behavior
•
2) Advances in chemistry as well as a major advancement in drug delivery
influenced the potency of drugs
– Opium was purified to morphine
– Coca was purified to cocaine
•
Hypodermic syringe was invented in 1858.
– Allowed purified drugs to be injected directly into blood stream
•
Civil war soldiers often developed opiate addictions
– Soldier’s Disease
• 3) increasing availability
of purified drugs,
combined with lack of
drug control laws led to
growing use in many
forms.
• Cocaine was a major
ingredient in a variety of
tonics
– Vin Mariani – Wine with
coca (1863)
– Coca cola (1886)
• Heroin synthesized by
Bayer laboratories
– Nonaddictive cough
remedy
– Meant to substitute for
codeine.
• 4) Medicalization of drug addiction
(second half of twentieth century)
– Addiction viewed as a disease
– Addicts should be treated by medical
association
• Modern view continues
– Alcoholics anonymous (AA)
– Narcotics anonymous (NA)
– National Institute on Drug Abuse (NIDA)
Drugs and the law
• The federal government is strongly against
legalization or decriminalization of
currently illegal drugs.
• Began with passage of the Pure Food and
Drug Act (1906)
– Mandated accurate labeling
Harrison Act (1914)
•
Regulated the dispensing and use of
opiates and cocaine
1. Use only for medical purposes
2. Pharmacists and physicians must be
registered with treasury dept. and keep
records of their inventory
3. Those selling the drug must pay a tax
4. Patented medicines with small amounts of
opiates or cocaine remained legal.
Consequences of Harrison Act
• Addiction not considered a disease at this
point, so patients that had been getting
drugs from physicians to maintain their
addiction were cut off.
– Turned to the street
– drug prices sky rocketed
What is addiction?
• Early views focused on physical
dependence
– Physical withdrawal symptoms
• Alcohol (Delirium Tremens)
• Opiates (kicking the habit; cold turkey)
– Prescription meds?
More recent view of addiction
• Compulsive drug seeking behavior
– Drug craving
• Chronic relapsing disorder
– Individuals are considered still addicted even
when in remission (drug-free period)
– There are often relapses
• Drug use persists despite harmful
consequences to the addict
– Physical
– Social
• American Psychiatric Association has
stopped using the term addiction and addict
in their professional writing
– Due to bad connotation
• Dirty heroin addicts
• Crack heads
• They use the term substance related
disorders
– Two general disorders
• Substance Dependence (more severe)
• Substance Abuse
• Note that merely using a drug, even if it is
illegal, does not necessarily indicate a
substance related disorder
• The use must be maladaptive
• There are also substance induced
disorders
– Cocaine psychosis
– Amphetamines
Progression of drug use
• Gateway theory
– Alcohol and cigarettes are gateways for
marijuana
– Marijuana is gateway for other illicit drugs
Box 8.1 The “Gateway” Theory of Drug Use
Problems with Gateway Theory
• 1) Population studied is usually
highschool students
– Given surveys
• Probably not hard-core users
• Hardcore users drop out.
• When heavy users of illegal drugs are studied it
has been shown that marijuana is often used prior
to other “hard” drugs
– But marijuana is often used before alcohol and tobacco.
• 2) These studies are correlational
– Correlation does not imply causation
– Does the fact that marijuana use reliably
precedes the use of “hard” drugs mean that
marijuana use causes abuse of harder drugs?
• What else could be playing a role?
Continuum of drug use
•
drug use also occurs along a continuum
–
Some people that experiment with drugs do not continue to substance abuse or dependence
•
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–
•
Drugs are not instantly addictive
Some people do
Why some do and some don’t is an important research question.
Also people can move in both directions along the continuum.
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–
They don’t necessarily have to fall farther and farther into abuse.
They can move in a direction of less problematic use or abstinence
8.5 Patterns of opioid drug use over a 20-year period in ten heroin addicts
• This slide supports
the view that
addiction is a chronic
relapsing disorder
• It also shows how
many drug users
move along the
continuum of drug
use
Which drugs are most addictive?
• Two sets of standards
– Legal standards
• Set by the Controlled Substances Act of 1970
• Five different schedules of drugs
– Note that alcohol and nicotine are not on the drug
schedule
– Can be bought without prescription
– Scientific standards
• Reflected by expert views of addictive potential
• Two experts rated abuse
potential of various drugs
– Jack Henningfield, formerly
Chief of Clinical
Pharmacology at the
Addiction Research Center
at NIDA
– Neil Benowitz, addiction
researcher at University of
California at San Francisco
• 1) presence and severity
of withdrawal
• 2) how reinforcing the
drug is (from human and
animal studies)
• 3) the degree of tolerance
produced by the drugs
• 4) degree of dependence
– Difficulty quitting
– Relapse
• 5) degree of intoxication
• Overall rankings
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Heroin (1.9)
Alcohol (2.5)
Cocaine (2.65)
Nicotine (3.35)
Caffeine (5.0)
Marijuana (5.4)
• Two of the top 4 substances
are legal
• Marijuana is lowest on this list,
but a schedule 1 drug.
• Keep in mind long term
consequences were not
included.
• Note that low numbers
indicate the most serious
abuse potential
• Also note how closely the
two experts rated the
drugs on the various
measures
Models of Drug Abuse and Dependence
• The physical dependence
model
• Once physically
dependent, attempts at
abstinence lead to
unpleasant withdrawal
symptoms
• Thus, the person is
motivated to take the
drug again.
– Negative RF
• Take drug (behavior)
• Remove withdrawal
(consequence)
• Wikler (1980) posited that
withdrawal could be classically
conditioned
• Certain contexts where drug
seeking behavior occurs can
become associated with
withdrawal.
– They are there to find drugs,
so they are likely in an
abstinence state
• Thus, an addict could be free
from acute drug withdrawal,
but experience withdrawal
exposed to the right
environmental stimuli (CS)
– Note that drug craving is part
of the CR
• Cocaine dependent individuals
show increased desire to get
high, and craving for cocaine
after seeing a video of a
person obtaining and then
smoking crack cocaine.
• Blue lines are controls (never
taken cocaine).
• Notice that the y-axis
represents a change score.
The cravings went up when
confronted with drug stimuli
Critique of physical dependence model
• 1) Some drugs do not cause physical
dependence but remain highly addictive
– Cocaine
• 2) The model does a good job of
explaining drug taking behavior after a
person has become dependent
– but doesn’t do a good job of explaining the
drug use that led to dependence in the first
place
• 3) Has difficulty explaining high levels of
relapse following drug detoxification.
– Wikler attempts to explain using his
conditioned withdrawal model
• Evidence that withdrawal symptoms associated
with environmental stimuli causing renewed drug
use is limited.
• Drug cravings are often considered more
psychological, rather than a physical withdrawal
symptom.
Positive Reinforcement model
• Unlike the physical
dependence model that
focused on negative
reinforcement this model
focuses on positive
reinforcement.
• A lot of animal work has
shown the reinforcing
properties of drugs
• One very important
procedure is selfadministration
4.23 Rat in an operant chamber
4.24 The drug self-administration method
Progressive-ratio schedule
• Allows researchers to measure
how reinforcing different drugs
(or different doses of drugs)
are relative to one another
• 1) CRF schedule (continuous
reinforcement)
– Every bar press = drug
injection
• 2) once well trained you can
test with a progressive ratio
– Keep increasing the FR (fixed
ratio) required to get the
injection
– Determine break point
• Most drugs that humans abuse will be selfadministered by animals.
• If animals are given unlimited access to cocaine
they can take so much drug as to cause
seizures
– Don’t eat
– Stop grooming
– Can die
• Most studies limit drug taking sessions to a few
hours per day.
• Why are abused drugs rewarding?
– Hijack the reward pathway?
– Neural mechanisms of reward
– Discovered with intracranial self stimulation
(ICSS)
• Olds and Milner (1954)
• Interaction between drugs of abuse and ICSS
– Researchers determine how much current is required to be rewarding
(cause lever pressing)
• The lower the threshold = more sensitive reward circuit
– Drugs of abuse lower the threshold for ICSS
• Indicates that the drug is working on the same neural pathway as the ICSS
– Withdrawal increases threshold
• Analogous to negative mood states in human withdrawal?
• Drugs that acutely reduce the threshold for ICSS
also increase synaptic DA levels in the nucleus
accumbens
– Enhancing firing of VTA neurons
• Opiates
• Nicotine ethanol
• THC
– Inhibiting reuptake or increasing release at terminals
• Cocaine
• amphetamine.
• Keep in mind that DA release in the nucleus
accumbens is not necessarily the only factor in
the rewarding properties of drugs
– Lesion mesolimbic pathway (VTA-NA)
• 6-OHDA in NA
• Abolishes self administration of cocaine and amphetamine
• Animals will still self administer alcohol and heroin.
– For some drugs there is more to reward than just the
mesolimbic pathway
Incentive-sensitization model of drug addiction
•
Distinguishes between drug liking (high)
and drug wanting (craving)
•
With repeated drug use drug wanting
increases, even though drug liking does
not increase (and may even decrease).
•
According to the model, different brain
regions control liking and wanting.
•
Repeated drug use sensitizes wanting
–
No sensitization and perhaps tolerance to
liking.
•
Perhaps mesolimbic pathway is more
important for drug wanting than drug
liking?
•
The brain changes associated with drug
wanting are long lasting. Leading to high
relapse rates
Opponent Process model
• This was originally posited as a general approach to
understanding motivation
• Strong emotions one way will cause swings of strong
emotions the other way when the stimulus is removed
– Jump out of airplane = strong sense of fear
– Followed by intense pleasurable sense of relief when you land
safely.
• Drugs = intense pleasurable high followed by unpleasant
withdrawal
– Euphoria followed by depression
• a process = manifest affective episode
• b process = underlying opponent process
• a process last for the duration of the episode
– Time falling from plane
• b process starts a little later and lasts longer
• a-b = top part of the following graph.
– Indicates the swing in affect just after the stimulus is
removed
• Land on the ground
• After many times
jumping from the
plane
– a process is
reduced
– b process is
enhanced
• Thus, the pleasure
of jumping from a
plane is greater and
the fear much
reduced
• How would this work
with drugs as an
example?
• Similar to incentive
sensitization model?
Critique of incentive-sensitization and opponent-process models
• They are the more modern view
• Both preferable to physical dependence
and positive reinforcement models.
– Incentive sensitization probably does a better
job of explaining drug craving
– Opponent-process seems to do a better job of
explaining the dysphoria associated with
abstinence
The disease model of addiction
• Widely accepted
– World health organization
– American medical association
• Two kinds of disease models
– Susceptibility models
– Exposure models
• Susceptibility models
– Inherited suceptibility
to uncontrolled drug
use.
– Loss of control - start
drinking = can’t stop
until intoxicated
• Exposure models
– Emphasize the brain
alterations that occur
with prolonged drug
use.
Critique of disease model
• There is no laboratory test that can identify the underlying cause of
the disease.
– It is defined only by its symptoms
• This is an old argument in the psychiatric and psychological
literature
– Do we treat underlying causes
• Can’t simply treat symptoms, have to find the underlying reasons
– Freud
– Do we treat symptoms
• If you cure the symptoms is there still a disease?
– Behaviorists
• Many psychological disorders are defined simply by their symptoms.
– DSM IV – TR
– We do not know what causes the disorder
Critique of disease model cont.
• Use of drugs occurs
on a continuum.
There is no clear
distinction between
nonaddictive behavior
and addictive
behavior
– Obesity
– Blood pressure
• The cut off points are
somewhat arbitrary
Toward a comprehensive model of drug abuse and dependence
• Pulling everything together
• It is important to understand what leads to
initial experimentation with drugs
– These factors may be very different from what
maintains drug use later in life
• It can take years to decades for dependence to
develop
• Implies initial use factors different from abuse
factors
Three factors involved in experimental drug use
• According to Petraitis et al. (1995).
– Three types of factors
• Social/interpersonal
• Cultural/attidudinal
• Intrapersonal
– Three levels of influence
• Proximal
– most direct influence
• Distal
– Not as predictive of immediate drug use as proximal, but more
so than ultimate.
• Ultimate
– not immediate influence but may determine long term risk
Factors involved in the development and maintenance of drug use
• Drug related factors
– Reinforcing effects of the drug
• Examples
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–
–
–
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Euphoria
Mood elevation
Relief from withdrawal
Relief from anxiety
Functional enhancement
» Ritalin and Adderall (study drugs)
Drug related factors cont.
• Discriminative subjective effects of drugs
– Produce internal states that can serve as
cues to control animal behavior
• Used to study how similar drugs are for an animal.
– Train to nose poke with amphetamine, but not saline
– Test with cocaine?
– Considered analogous to the subjective
effects that people experience when they take
a drug.
Drug related factors cont.
• Certain environments may become associated
with drug states
– The person or animal expects to feel drug effects in
that environment
• Could contribute to drug seeking behavior
• Soldiers addicted to heroin in Vietnam often
stopped taking the drug when they returned
home.
– Apparently with less difficulty
– Perhaps because removed from the environmental
cues associated with the drug
Drug related factors cont.
• Aversive affects of drugs
– We all know that drugs can have aversive
effects
• Alcohol – hangover
• Cocaine – anxiety
– These effects apparently do not override the
positive effects
• Heroin – good sick
Risk Factors
• Stress and the ability of the person to cope
with stress
– People under stress often relapse
– Animals will increase self administration under
stress
• Comorbidity
– Often psychological disorders are associated
with increased substance use.
Risk Factors cont.
• Familial and sociocultural influences
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Adult children of alcoholics = increased risk
Social facilitation – alcohol with friends
Escape from social responsibilities
Group solidarity – some cultures identify with heavy alcohol use
• Irish?
• Russians?
– Drug subculture?
• Reject “straight” lifestyle and social norms.
• Genes
– Inherited characteristics may influence abuse potential
Protective factors
• How to help abusers remain abstinent
– Avoid drug related cues
– New social groups
– Life structure
8.17 Factors involved in the development and maintenance of compulsive drug use