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COGNITIVE
SCIENCE
17
Drug Abuse or …
Drug Abuse or…
For Big Kids
Mike Datko, B.S.
Features of drug abuse and addiction
• Definition: how are abuse and addiction
defined clinically?
• Positive reinforcement
• Negative reinforcement
• Opponent process theory
• Craving and relapse
Clinical definitions
•
Drug abuse is defined by the Diagnostic and Statistical Manual of Mental Disorders
–
A. A maladaptive pattern of substance use leading to clinically significant impairment or
distress, as manifested by one (or more) of the following, occurring within a 12-month period:
–
1. Recurrent substance use resulting in a failure to fulfill major role obligations at work,
school, or home (e.g., repeated absences or poor work performance related to substance use;
substance-related absences, suspensions or expulsions from school; neglect of children or
household)
–
2. Recurrent substance use in situations in which it is physically hazardous (e.g., driving
an automobile or operating a machine when impaired by substance use)
–
3. Recurrent substance-related legal problems (e.g., arrests for substance-related
disorderly conduct)
–
4. Continued substance use despite having persistent or recurrent social or
interpersonal problems caused or exacerbated by the effects of the substance (e.g.,
arguments with spouse about consequences of intoxication, physical fights)
–
B. The symptoms have never met the criteria for Substance Dependence for this class of
substance.
A state of drug dependence is defined similarly, with the additional requirement of
the manifestation of physical withdrawal symptoms when drug use is stopped.
Koob (at UCSD) described addiction as involving “a cycle of spiraling dysregulation
of brain reward systems that progressively increases, resulting in the compulsive
use and loss of control over drug taking.”
Positive reinforcement
• An increase in the future frequency of a
behavior due to the addition of a stimulus
immediately following a response. (from
Wikipedia)
• If a person has a positive experience as a
result of taking a drug, and subsequently takes
more of the drug in the future, it is called
positive reinforcement.
Negative Reinforcement
– Relief from withdrawal symptoms
– If no withdrawal symptoms are present, relief
from stress caused by emotional or life
circumstances (or more generally, compensating
for or reversing some physiological)
– Example: Someone who drinks alcohol or takes
other anxiolytic (anxiety-relieving) drugs to relieve
naturally occurring anxiety is experiencing
negative reinforcement.
Opponent-process theory
• Initially, positive effects of
a drug easily outweigh
negative effects.
• Net effect of taking a drug
is very positive.
• As usage continues,
homeostatic
mechanisms become
better at counteracting
the acute effects of the
drug.
• Net effect is still
positive, but less and
less so.
• At this point, positive
effects of drug are equal
to body’s homeostatic
response.
• In late stages of addiction,
homeostatic “set point” has
changed (a phenomenon
called allostasis).
• Net effect is neutral
(must have drug to feel
normal).
• Net effect of drug use is
negative, and the user must
have the drug in order to
prevent very negative
feelings.
Diagrams from Neurotopia.com
• Addictive potential of a drug is related to its
chemical properties as well as it’s route of
administration.
• Route of administration affects how quickly
drug enters bloodstream.
- Some routes, from fastest to slowest:
• Intravenous injection, smoking, nasal insufflation,
drinking/eating
• Chemical properties of drug affect how
easily/quickly it crosses the Blood Brain Barrier
once its in the bloodstream.
Amphetamine
Methamphetamine
Craving and Relapse
• Incentive salience – Stimuli associated
with drug taking become exciting and
motivating – they become a
provocation to act (from your book, pg.
618).
– Craving is triggered in people with a
history of drug abuse after exposure to
drug-related stimuli (pictures,
paraphernalia, smells, locations, people)
• Brain areas involved in craving:
– Medial Prefrontal Cortex and Nucleus
Accumbens
– In users, these areas show greater
responses to drug-related cues than in
non-users, but are less active at rest in
users than in non users.
Common Drugs of Abuse and their
Effects
• Opiates
• Stimulants
– Cocaine
– Methamphetamine
• Nicotine
• Alcohol
• Cannabis
http://learn.genetics.utah.edu/content/addiction/drugs/mouse.html
Opiates
• Primarily heroin and
oxycodone (most addictive)
– Also, morphine, hydrocodone
(Vicodin), methylmorphine
(codeine)
• Acute positive effects:
euphoria, relaxation,
analgesia (pain relief)
• Acute negative effects:
constipation, depressed
breathing and heart rate
(overdose can result in death
because of this).
• Opiates – site/mechanism of action:
– Mu and delta opiate receptor agonist.
• Mimics the effects of the body’s naturally occurring endorphins
(but much stronger effect because concentrations are usually
higher than those of endorphins)
• Activation of opiate receptor inhibits release of GABA from an
interneuron
– Inhibits the inhibition (from GABA) on a neighboring neuron, which
then releases more dopamine than usual to a post-synaptic neuron.
(detailed diagram on next slide).
– Studies with KO mice that lack mu-opiate receptor
• KO mice do not develop conditioned place-preference or
certain withdrawal symptoms.
Stimulants: Cocaine and
Methamphetamine
• Sites of action:
– Cocaine: inhibits dopamine reuptake in the
synapse – dopamine sits in synapse for longer
time and at higher concentrations.
– Methamphetamine (and regular amphetamine):
Causes vesicles containing dopamine to rupture
within the presynaptic neuron and reverses the
action of dopamine reuptake channels.
Stimulants – effects of abuse
•
Figure 18.10 in book (pg 627) – after 25 days, close to 100%
fatality rate in rats allowed to freely administer cocaine (vs
40% fatality rate for heroin).
•
Chronic users often develop hallucinations, delusions of
persecution, mood disturbances, and repetitive behaviors
which strikingly resemble symptoms of schizophrenia (role of
dopamine system?).
•
Figure 18.12 (pg 628) – significantly lower concentrations of
dopamine transporters, as measure with PET, in meth
abusers compared to controls.
– one issue with this type of study is the ambiguity of the cause of
reduced dopamine transporters/dopaminergic terminals – did meth
abuse cause this difference or was it the result of previously existing
factors such as genetics (in which case, did these genetic differences
predispose the individual to drug abuse?)?
•
•
Figure 18.14 (pg 629) – significantly lower dopamine
receptors in striatum of meth abusers.
Damaged dopamine system = higher risk of developing
Parkinson’s Disease as age increases?
Nicotine
• Mechanism of action:
– Agonist at nicotinic acetylcholine receptors.
– Ionotropic receptor (rapid effects of activation)
– Most nicotinic receptors are heteroreceptors on postsynaptic
neurons (their activation causes the release of other
neurotransmitters into the synaptic cleft).
• Nicotine is responsible for addiction and craving
associated with cigarettes, but is not the major
cause of health problems.
– Other ingredients and carcinogens found in smoke
lead to cancer and cardiovascular problems.
– Nicotine alone is only toxic in high doses
Alcohol
• Mechanism/site of action:
– Indirect agonist at GABA-A receptors and indirect
antagonist at NMDA receptors.
• Produces both positive and negative
reinforcement:
– Mild euphoria, rise in dopamine in NAC: positive
reinforcement
– Reduction of anxiety (GABA actions): negative
reinforcement
• Unlike with most drugs, severe withdrawal
symptoms from alcohol can be fatal.
– Convulsions and seizures result from a
hypersensitization of NMDA receptors that occurs
with long-term alcohol use.
• Long-term use leads to lower amounts of
dopamine receptors in the striatum.
• Korsakoff’s syndrome – anterograde and
retrograde amnesia, apathy, and other symptoms
– Result of thiamine deficiency that often occurs as a
result of alcoholism
Cannabis
• Main psychoactive compound is
Tetrahydrocannabinol (THC)
• Mechanism/site of action – agonist at CB1
receptors.
– CB1 receptors are normally sensitive to
endogenous cannabanoids like anandamide.
– Like other drugs of abuse, use leads to
temporary increase in dopaminergic activity in
key areas
– Hippocampus contains a large concentration of
CB1 receptors
• May explain effect of cannabis on memory formation
• One of the few drugs of abuse that has
extremely low overdose potential.
– Very low concentrations of CB1 receptors in
brain stem
Treatments and Therapies
• Opiates –
– Methadone: mu-opiate receptor agonist
• Has effects similar to heroin but administered in a
controlled setting (clinic, by nurses/doctors) and taken
in liquid form.
– Buprenorphine: mu-opiate partial agonist
• Competes at same receptor as normal opiates but
produces much less of an effect when it binds.
Treatments: stimulants
• Immunotherapy:
– Create and administer proteins that make the
immune system attack a given drug.
• For example, giving someone a dose of proteins that
resemble cocaine but are not actually cocaine will train
their immune system to eliminate actual cocaine as if it
were a disease-inducing virus.
• Gamma-vinyl GABA (GVG) – GABA receptor
agonist that reduces the reinforcing effects of
cocaine.
Treatments: Nicotine
• Nicotine gum and patch:
– Maintains a constant level of
nicotine to avoid withdrawal
symptoms, but does not produce
a “nicotine buzz” because it takes
much longer to enter the
bloodstream than smoked
nicotine.
• Bupropion (Wellbutrin, Zyban) –
Catecholamine reuptake
inhibitor that reduces cravings.
Treatments: Alcohol
• Ro15-4513 prevents intoxication by blocking alcohol
binding site on GABA-A receptor.
– NOT used because it would enable people to potentially drink
toxic amounts of alcohol without feeling any noticeable effects.
• Naltrexone – opiate receptor antagonist
– Alcohol induces the release of endogenous opioids
(endorphins).
– Davidson, Swift, and Fitz (1996) study with social drinkers –
found that subjects who were taking naltrexone prior to a
drinking session drank slower and drank less than controls.
• Acamprosate – NMDA receptor antagonist
– Eases withdrawal symptoms and makes alcoholics less likely to
drink again after treatment.
Other facts/info
• The majority of people who try addictive
drugs do not become addicted.
• Heredity (genetics) seems to dictate who
becomes addicted after trying a drug, but
environment (friends, family, etc.) is a more
important factor in determining whether or
not someone will try a drug initially.