Drugs and Addiction
Drugs and Addiction
What is a drug?
– An exogenous substance that, when absorbed into the body of a
living organism, alters normal bodily function
What are psychoactive drugs?
– Drugs that influence subjective experience and behavior by
acting on the nervous system
How are drugs administered?
– Drugs are typically administered in one of four ways:
Oral Ingestion (e.g. alcohol)
Injection (e.g. heroin)
Inhalation (e.g. tobacco)
Absorption through Mucous Membranes (e.g. cocaine)
Mechanisms of Drug Action
Psychoactive Drugs
influence the CNS is
many ways, including:
– Binding to pre- and
postsynaptic receptors
– Influencing synthesis,
transport, release, or
deactivation of
neurotransmitters
– Influencing the chain of
chemical reactions
elicited by the activation
of postsynaptic receptors
Drug Metabolism
Most drugs are deactivated by enzymes synthesized by
the liver.
– Drug Metabolism
Process by which liver enzymes covert active drugs to non-active
forms.
Typically enzymes covert drugs into a more hydrophilic form,
preventing the drug from being able to pass through the lipid
membranes of cells.
– Drug Elimination
Small amounts of some psychoactive drugs are passed out of the
body in urine, sweat, feces, breath, and mother’s milk
Drug Tolerance
Drug Tolerance
State of decreased sensitivity to a drug that develops as a result
of exposure to it.
Drug tolerance can be shown in two ways:
– A given dose of a drug has LESS of an effect than that
before exposure to it.
– A HIGHER dose of a drug is required to produce the same
effect.
Drug Tolerance
Drug Tolerance
– A shift of the dose-response curve (fig. 15.1) to the right.
Drug Tolerance
Cross Tolerance
– One drug can produce tolerance to other drugs that act by the
same mechanisms
Drug Sensitization
– Increasing sensitivity to a drug
A given dose of a drug has MORE of an effect than it had
before exposure to it.
A LOWER dose of a drug is required to produce the same
effect.
Drug Tolerance
Drug Sensitization
– A shift of the dose-response curve (fig. 15.1) to the left.
Drug Tolerance
Metabolic Tolerance
– Drug tolerance that results from changes that reduce the amount of
the drug getting to its sites of action.
E.g. liver increases the production of enzymes that metabolize a
drug
Functional Tolerance
– Drug tolerance that results from changes that reduce the reactivity of
the sites of action to the drug.
E.g. reduction in the number of receptors for a drug
– Tolerance to psychoactive drugs is largely
functional
Drug Withdrawal
Withdrawal Syndrome
– Occurs when significant amounts of a drug that have been in the
body for a period of time suddenly decrease.
E.g. long-time smokers attempt to quit by going “cold turkey.”
– Withdrawal effects are opposite the initial effects of the drug (fig.
15.2).
– Individuals that suffer withdrawal reactions when they stop taking a
drug are Physically Dependent.
Role of Learning in Drug
Tolerance
Contingent Drug Tolerance
– Tolerance develops only to drug effects that are actually
experienced.
Role of Learning in Drug
Tolerance
Conditioned Drug Tolerance
– Tolerance effects are maximally expressed only when a drug is
administered in the same situation in which it has previously been
administered.
Group A – tested in
different context as
drug administration
Group B – tested in
same context as
drug administration
Role of Learning in Drug
Tolerance
Conditioned Drug Tolerance
– Tolerance effects are maximally expressed only when a drug is
administered in the same situation in which it has previously been
administered.
Conditioned Compensatory Responses
– Stimuli that predict drug administration elicit conditional responses
opposite the effects of the drug.
Exteroceptive stimuli
Interoceptive stimuli
– Views every drug administration as a Pavlovian conditioning trial.
Five Commonly Abused Drugs
Tobacco
Alcohol
Marijuana
Cocaine
Opiates
Five Commonly Abused Drugs
Tobacco
– Nicotine
The major psychoactive ingredient of tobacco.
– Stimulates nicotinic ACh receptors
Highly addictive
– About 70% of those who experiment with smoking become
addicted.
– Compare to 10% with alcohol and 30% for heroin
Only about 20% of attempts to stop smoking are successful.
Tobacco
Effects of Long-Term Tobacco Use
– Smoker’s syndrome – chest pain, labored breathing, wheezing,
coughing, increased susceptibility to respiratory infections
– Susceptible to various lethal lung disorders – pneumonia, bronchitis,
emphysema, lung cancer
– Buerger’s disease
– Some good news: quitting smoking by age 40 adds an average of 9
years to life span
Five Commonly Abused Drugs
Alcohol
– A depressant
– Heritability estimate for alcohol addiction is about 55%
– Metabolic and functional tolerance develops
– Attacks almost every tissue in the body
Alcohol
Effects of Chronic Alcohol Consumption
– Severe withdrawal in three phases:
5-6 hrs post-drinking: tremors, nausea, sweating, vomiting, etc.
15-30 hrs: convulsive activity
24-48 hrs: delirium tremens (DTs) – may last 3-4 days
– The convulsions and DTs can be fatal
– Korsakoff’s syndrome
– Cirrhosis
– Fetal alcohol syndrome
Alcohol
Alcohol and the Brain
– Reduces flow of Ca2+ into neurons
– Interferes with 2nd messenger systems
– Disrupts GABAergic and glutaminergic transmission
– Triggers apoptosis
Five Commonly Abused Drugs
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 of long-term use are far less severe than those
associated with alcohol and tobacco
Five Commonly Abused Drugs
Marijuana
– THC binds to endogenous cannabinoid receptors (CB receptors.)
CB1 receptor is the most common G-protein linked receptor in
the brain.
CB2 receptor is found in the brain stem and in cells in the
immune system.
– Cannabinoid receptors are found on pre-synaptic neurons!
endocannabinoids are released from the post-synaptic neuron,
and bind to CB receptors on the pre-synaptic neuron, acting as a
retrograde neurotransmitter.
Five Commonly Abused Drugs
Marijuana
Marijuana
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
– Possible correlation between marijuana use and schizophrenia, but
no causal link has been shown
Marijuana
Medicinal Uses of Marijuana
– Treats nausea
– Blocks seizures
– Dilates bronchioles of asthmatics
– Decreases severity of glaucoma
– Reduces some forms of pain
Five Commonly Abused Drugs
Stimulants
– Increase neural and behavioral activity
– Cocaine, Amphetamine, MDMA – commonly abused
– Crack – a potent, cheap, and smokable form of cocaine
– Cocaine is an effective local anesthetic
Synthetic analogues procaine and lidocaine used today
Stimulants
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 mild
Stimulants
Cocaine
– Blocks the re-uptake of dopamine by the dopamine re-uptake
transporter
Stimulants
Other Stimulants
– Stimulants are neurotoxins
– Amphetamine (“speed”)
Effects like cocaine – can produce psychosis
– MDMA (“ecstasy”)
Impairs dopaminergic and serotonergic function in animal
studies; human relevance unclear
Impairs executive function, inhibitory control, and decision
making (as shown by cortex and limbic functional brain scan
abnormalities)
Five Commonly Abused Drugs
Opiates: Heroin and Morphine
– The endogeneous chemicals that bind to opiate receptors are called
endorphins, and there are at least 20 different kinds of endorphins.
– Morphine and codeine, which also bind to these receptors, are drugs
obtained from the opium poppy
– Medicinal uses
Analgesics (painkillers)
Treatment of cough and diarrhea
– High risk of addiction
Opiates: Heroin and Morphine
U.S. Opiate History
– Opium was 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
Opiates: Heroin and Morphine
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
Opiates: Heroin and Morphine
Prevalence of drug use in the United States
Reducing Drug Abuse
Current approaches (e.g. War on Drugs) are not effective
What recommendations would you make to decrease the
incidence of drug abuse?
Which abused drugs should we be most concerned about?
Addiction
What is addiction?
– Habitual drug use despite its adverse effects on health, social life,
and despite repeated efforts to stop.
Drug addicts are habitual drug users.
Not all habitual drug users are addicts.
Is addiction the same thing as physical dependence?
– NO!
– Drug addicts will renew drug taking even after withdrawal effects
have subsided.
Biopsychological Theories of
Addiction
Physical-dependence theory
– dependence due to pain of withdrawal
– Addicts caught in a cycle of drug taking, withdrawal, drug taking
to relieve withdrawal.
– Detoxified addicts
No longer have drugs in their system and do not experience
withdrawal symptoms
does not explain why…
– addicts relapse long after detoxification
– individuals begin using drugs
– addictions develop to drugs that do not produce severe
withdrawal symptoms
Biopsychological Theories of
Addiction
Positive-incentive theories
– The primary factor in most cases of addiction is the craving for a
drug’s pleasurable effects.
must explain…
– the difference between the hedonic value and the positive
incentive value of the drug
– the transition from being a drug user to becoming a drug addict
Biopsychological Theories of
Addiction
Incentive-sensitization theory
– Positive-incentive value (wanting)
the anticipated pleasure of taking a drug
– Hedonic value (liking)
the actual pleasure experienced
– With drug use, the positive-incentive value increases due to memory
of the pleasure of early drug experience
– The hedonic value decreases due to drug tolerance
– Result: addicts crave drugs more and enjoy them less
Causes of Relapse
Stress
– drug use as a coping mechanism
Priming
– a single exposure leads to a relapse
Environmental cues
– Conditioned drug tolerance
– Returning to place where drugs once taken (or even thinking about
drug) causes conditioned compensatory responses, craving, and
relapse
Intracranial Self-Stimulation and
Brain “Pleasure Centers”
Reward Circuits
– Brain circuitry exists that reinforces behaviors
– Many species will work for stimulation of brain “pleasure centers”
– Discovered by Olds and Milner (1954)
Proposed that the same brain regions are activated by natural
rewards, such as food, water, and sex.
– Drug use may be reinforced by acting on this circuitry
Intracranial Self-Stimulation (ICSS)
Fig. 15.6 A rat pressing a lever to obtain rewarding brain stimulation
Mesotelencephalic Dopamine
System and Self-Stimulation
Dopaminergic neurons projecting from two midbrain
areas to telencephalon
– Nigrostriatal pathway
Substantia nigra neurons projecting to dorsal striatum
– Mesocorticolimbic pathway
Ventral tegmental area neurons projecting to cortical and
limbic sites, including the nucleus accumbens
This is the major “reward” pathway for ICSS, natural rewards,
and addictive drugs
Fig. 15.7 Mesotelencephalic dopamine system of the human brain
Mesocorticolimbic Pathway and
Reward
Evidence that the mesotelencephalic pathway plays an
important role in ICSS.
– Self-stimulation sites that do not contain dopaminergic neurons
project to the mesotelencephalic dopamine system
– Increase in dopamine release seen in the mesocorticolimbic
pathway following self-stimulation (fig. 15.8).
– Dopamine agonists tend to increase self-stimulation and
antagonists to decrease self-stimulation
– Lesions of the mesocorticolimbic pathway disrupt self-stimulation
Two Ways to Measure Drug
Positive Incentive in Animals
Drug self-administration paradigm
– Lab animals press a lever to inject drugs into themselves
through cannulas (thin tubes) implanted in the brain
Conditioned place-preference paradigm
– Lab animals choose to spend more time in the cage
compartment where drugs were administered, compared to a
compartment not associated with drug administration.
Behavioral Preference Tests
Fig. 15.9
Dopamine and Drug Addiction
Evidence of the Involvement of Dopamine in Drug
Addiction
– Dopamine’s role suggested by self-stimulation studies
– Dopamine antagonists interfere with self-stimulation and reduce
the reinforcing effects of food
– Nucleus accumbens appears to play a primary role
Nucleus Accumbens (NA) and
Drug Addiction
Evidence of the Involvement of the Nucleus Accumbens
in 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 self-administration or
drug-related place preference
– Both self-administration of addictive drugs and natural reinforcers
result in increased dopamine in the NA
Dopamine release: Reward or
Expectation of Reward?
Reward:
Ventral tegmental neurons fire in response to a stimulus at a rate
proportional to its reward value
Expectation of Reward:
Neutral stimuli that predict a reward can trigger dopamine
release in the NA
Current view:
An increase in the activity of dopaminergic neurons in the ventral
tegmental area occurs:
– when a conditional stimulus predicts a reward
– when a reward is presented in an unpredictable fashion
Structures That Mediate
Addiction: The Current View
Initial drug taking
– involves activation of the mesocorticolimbic pathway (nucleus
accumbens), prefrontal lobes, and amygdala
Craving and compulsive drug use
– Involves activation of the dorsal striatum and hypothalamic stress
circuits
Relapse
– stress (hypothalamic stress circuits)
– priming doses (prefrontal cortex)
– drug associated cues (amygdala)