Download Chapter 18

Drug Abuse
Chapter 18
Copyright © Allyn & Bacon 2010
ALCOHOL
 http://www.youtube.com/watch?v=oax3cUFsBSw
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DRUG STATS IN CANADA
 Among Canadians 15 years and older, the prevalence of past-year
cannabis use is 10.7% in 2010.
 Among Canadians 15 years and older, the prevalence of past-year
cocaine or crack is 1.2% in 2010, past-year use of hallucinogens
(0.9%), ecstasy (0.7%) and speed (0.5%)
 The rates of psychoactive pharmaceutical use and abuse: 26.0% of
respondents aged 15 years and older indicated that they had used
an opioid pain reliever, a stimulant, or a sedative or tranquilizer in
the past year while 0.3% reported that they used any of these drugs
to get high in the past year.
 Among Canadians 15 years and older, the prevalence of past-year
alcohol use was 77.0%
 Cost – over 40 billion dollars!
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DRUG ABUSE IN NEWFOUNDLAND
 10% abstain from all alcohol use
 One of the highest rates of alcohol and drug
addiction than anywhere else in Canada.
 More then 13% are struggling with drug
addiction, alcoholism or both.
These numbers work out to approximately two hundred thousand people at any one
time are addicted to something.
 Police report that the number one cause of all
domestic abuse cases in NL can be linked back
to alcoholism and/or drug addiction.
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Lecture Preview
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Common Features of Addiction
Commonly Abused Drugs
Heredity and Drug Abuse
Therapy for Drug Abuse
COMMON FEATURES OF ADDICTION
 A Little Background
•
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Recreational Drugs – historically these are drugs
discovered that produce pleasurable effects.
One of the earliest recreational drugs was ethyl
alcohol. Others include:
•
•
•
•
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Opium
Cannabis
Coca
Coffee
Tobacco
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Drug
Sites of Action
Ethyl alcohol
NMDA receptor (indirect antagonist),
GABAa receptor (indirect agonist)
barbiturates
GABAa receptor (indirect agonist)
Benzodiazepines (tranquilizers)
GABAa receptor (indirect agonist)
Cannabis
CB1 cannabinoid receptor (agonist)
Nicotine
Nicotinic ACh receptor (agonist)
Opiates (heroin, morphine, etc)
μ and δ Opiate receptor agonist
Phencyclidine (PCP) and ketamine
NMDA receptor (indirect antagonist)
Cocaine
Blocks reuptake of dopamine (and 5-HT
and NE)
amphetamine
Causes release of dopamine (running
DA transporters in reverse)
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Cocaine Blocks DA Re-Uptake in the Pre-Synaptic Cell: a DA Agonist
Desire to
alleviate
withdrawal
symptoms
Drug effects
Consumption
Withdrawal
Come-down
Reward
COMMON FEATURES OF ADDICTION
 Positive Reinforcement
•
•
•
Addictive drugs have reinforcing effects
Effectiveness of a reinforcing stimulus is greatest if it
occurs immediately after a response occurs
Most addictive drugs are those that have immediate
effects
•
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Drug users prefer heroin to morphine not because effects are
different, effects are faster
Only a small percentage of people that try addictive
drugs become dependent
•
Cocaine is one of the most addictive drugs currently available,
~ 15% of people who use it become addicted
COMMON FEATURES OF ADDICTION
•
Neural Mechanisms
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Natural reinforcers (food,
water, sex) – cause release of
dopamine (DA) in the nucleus
accumbens (NAC) –
mesolimbic pathway
Amphetamine, cocaine,
opiates, alcohol, PCP,
cannabis all trigger release of
DA in NAC as measured by
microdialysis
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COMMON FEATURES OF ADDICTION
 Neural Mechanisms
•
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Drugs “hijack” brain mechanisms that normally help us
adapt to our environment
Addiction begins in mesolimbic DA system, produces
long-term changes in brain regions that receive input
from these neurons
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DA Pathway
COMMON MECHANISMS OF ADDICTION
 Neural Mechanisms
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Ventral tegmental area (VTA)
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Single injection of addictive drug increased strength of excitatory
synapses on DA neurons in VTA in mice
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Insertion of additional AMPA receptors into the postsynaptic membrane of
DA neurons
Single injection of drug produces synaptic strengthening in the
VTA lasting 5 days, if drug given longer (2 weeks), changes in
VTA persist
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COMMON MECHANISMS OF ADDICTION
 Neural Mechanisms
Due to changes in VTA, increased activation in regions
that receive DA input from VTA
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Ventral striatum
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Nucleus accumbens
Dorsal striatum
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Caudate nucleus and putamen
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COMMON FEATURES OF ADDICTION

Neural Mechanisms

At 1st, addict experiences the pleasurable effects of
drug, reinforcing behaviors (getting the drug, preparing
it, swallowing, injecting, sniffing, smoking it, etc)

Ventral striatum: nucleus accumbens
•
Early reinforcing effects that take place in NAC encourage drugtaking behavior
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COMMON FEATURES OF ADDICTION

Neural Mechanisms
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Subsequent compulsive behaviors in addiction occur
only after continued use of addictive drug

Dorsal striatum: caudate nucleus and putamen
•
Infusion of DA antagonist into dorsal striatum suppressed lever
presses that had been reinforced by light that had been paired with
cocaine
•
Presence of a light that had previously been paired with IV cocaine
increased DA release in the dorsal striatum, not ventral (NAC)
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COMMON FEATURES OF ADDICTION
 Neural mechanisms
•
In humans…
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When cocaine addicts are given an injection of
methylphenidate, they show a much smaller release of DA in
NAC or dorsal striatum than controls
•
When people who were addicted to cocaine watched a video of
people smoking cocaine
Increased release of DA was seen in dorsal striatum, not
ventral striatum
•
 The response to the drug itself is diminished in addicts,
but the response to cues associated with the drug is
augmented – in the dorsal striatum
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COMMON FEATURES OF ADDICTION
 Neural mechanisms
Orexin and MCH play a critical role in the reinforcing
effects of drugs
•
Orexin (synthesized in LH) is released in VTA, NAC, dorsal
striatum
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•
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Administration of addicted drugs or stimuli associated with them
activate orexin neurons
Infusion of orexin into VTA causes relapse
Block of orexin in VTA blocks cocaine seeking elicited by drugrelated cues and prevents CPP (place where morphine was
previously administered)
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COMMON FEATURES OF ADDICTION
 Neural mechanisms
Orexin and MCH play a critical role in the reinforcing
effects of drugs
•
MCH (synthesized in LH) – receptors in NAC
•
MCH neurons also contain DA receptors in NAC
Stimulating both DA receptors and MCH receptors increased firing
of NAC neurons
Block of MCH receptors decreased the effectiveness of cocaine or
cocaine-related cues of the animals’ behavior
•
•
•
•
Mutant MCH receptor had same effect
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COMMON FEATURES OF ADDICTION
 Negative reinforcement
•
A behavior that turns off (or reduces) an aversive
stimulus will be reinforced
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Not punishment – makes behavior less likely
Tolerance – decrease in sensitivity to a drug that
comes from repeated use
Withdrawal symptoms – primarily the opposite of the
effects of the drug
•
•
Effects of heroin – euphoria, constipation, relaxation
Withdrawal effects of heroin – dysphoria, cramping and
diarrhea, and agitation
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COMMON FEATURES OF ADDICTION
 Negative Reinforcement
•
•
•
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Tolerance – body’s attempt to compensate for unusual
condition
Drug disturbs normal homeostatic mechanisms in the
brain – compensatory responses
Because of this compensation, user must take
increasing amounts to achieve the original effects of
the drug
Mechanisms also cause withdrawal
•
When the person stops taking the drug, compensatory
mechanisms make themselves felt – unopposed by drug
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COMMON FEATURES OF ADDICTION
 Positive reinforcement seems to be what
provokes drug taking in the first place
 Reduction in withdrawal symptoms may play
a role in maintaining drug addiction
 Negative reinforcement may also explain
acquisition of drug addictions under some
conditions
•
Alcohol to relieve feelings of anxiety
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COMMON FEATURES OF ADDICTION
 Cravings and Relapse
•
When an addictive drug activates the mesolimbic DA system, it
gives incentive salience to stimuli present at that time
• Stimuli associated with drug become exciting and motivating
• Increases cravings
 Animal model of cravings
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Reinstatement
• Animals are first trained to make a response (press a lever), that
is reinforced by iv injections of drug (cocaine)
• Response is extinguished – injections of saline instead of
cocaine
• Once the animal stops responding (pressing the lever),
experimenter administers a “free” injection of drug
• In response, animals begin pressing lever again
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COMMON FEATURES OF ADDICTION
 Cravings and Relapse
•
Animal model – reinstatement
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Relapses produced by unexpected dose of drug activate
mesolimbic DA system
If the NAC or VTA of rats is temporarily inactivated, free shot of
cocaine fails to reinstate responding
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COMMON FEATURES OF ADDICTION
 Cravings and Relapse
•
Extinction – new form of learning, animal does not
forget to make a particular response, it learns not to
•
Ventromedial prefrontal cortex (vmPFC)
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Stimulation of vmPFC with infusion of AMPA blocked reinstatement
produced by free shot of cocaine
Dorsal anterior cingulate cortex (dACC)
•
Reinstatement of lever pressing for infusions of cocaine was
abolished by injecting a GABA agonist into dACC – region of dorsal
PFC that has excitatory connections with NAC
dACC plays a role in craving, vmPFC plays a role in
suppression
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COMMON FEATURES OF ADDICTION
 Craving and Relapse
•
In humans…
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Drugs of abuse or cues associated with them activate several
brain regions
•
Anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), insula,
dorsolateral PFC (dlPFC)
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COMMON FEATURES OF ADDICTION
 PFC
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Activity in mPFC of cocaine abusers was less active than that of
normal subjects
When addicts perform tasks that normally activate mPFC, mPFC
is less activated than that of healthy controls
Amount of activation of mPFC was inversely related to amount of
cocaine that cocaine abusers normally took each week
• lower brain activity, more cocaine
Drug abusers show the same deficits on tasks that involved PFC
as do people with lesions of PFC
Structural abnormalities of PFC in drug abusers
•
5-11% decrease in gray matter volume in PFC in chronic cocaine
abusers
• Abnormalities a result of drug use/addiction, or predisposing factor?
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COMMON FEATURES OF ADDICTION
 PFC
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Negative and cognitive symptoms of schizophrenia
result from hypofrontality
Similar to symptoms of long term drug abuse
High level of comorbidity of schizophrenia and drug
abuse
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~50% of schizophrenics have a substance abuse disorder
70-90% are addicted to nicotine
Prefrontal gray matter volumes were 10.1% lower in
alcoholic patients, 9% lower in schizophrenics, 15.6%
lower in patient with both disorders
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COMMON FEATURES OF ADDICTION
 PFC – judgment, risk taking, control of inappropriate
behaviors
 Adolescents are more vulnerable to drug addiction than
adults
 During adolescents, rapid increase in maturation of
neuronal circuits in brain – PFC
 Before maturation, adolescents display risky behaviors,
impulsive behaviors, experimentation with drugs
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~50% of cases of addiction begin between ages 15 and 18, very few
begin after age 20
Early onset of drug-taking is associated with more severe addiction
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COMMON FEATURES OF ADDICTION
 Craving and relapse
•
Stress!
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Stressful situations can cause former drug addicts to
relapse
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Socially defeated mice become more sensitive to the effects
of cocaine
Stress that occurs early in life can have long-lasting effects
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Stressed infant rats, as adults acquired a drug habit and took more drug
than controls (non-stressed)
CRH can reinstate drug-taking behavior
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Block of CRH receptors can reduce the likelihood of relapse from drugs or
drug cues
CRH receptors in VTA – infusion of CRH in VTA causes relapse, CRH
antagonist in VTA prevents reinstatement of drug-taking by a stressful
stimulus
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COMMON FEATURES OF ADDICTION
 Craving and relapse
•
Stress!
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CRH can reinstate drug-taking behavior
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Block of CRH receptors can reduce the likelihood of relapse from
drugs or drug cues
CRH receptors in VTA
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Infusion of CRH in VTA causes relapse
CRH antagonist in VTA prevents reinstatement of drug-taking by a
stressful stimulus
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COMMONLY ABUSED DRUGS
 Opiates
 Stimulant drugs
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•
Cocaine
Amphetamine
 Nicotine
 Alcohol
 Cannabis
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OPIATES
1. Heroin is illegal in most countries
2. Because of tolerance, people must take more
and more of the drug to produce the same
“high”
3. Use of unsanitary needles – hepatitis/AIDS
4. If addict is pregnant, her infant will also become
dependent on the drug (crosses the placental
barrier). Infant must be given opiates right after
birth and then weaned gradually
5. Uncertainty of strength of batch
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OPIATES
 Neural Basis of Reinforcing Effects
•
Analgesia, hypothermia, sedation, reinforcement
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Opiate receptors in PAG - analgesia
Opiate receptors in preoptic area – hypothermia
Opiate receptors in reticular formation – sedation
Opiate receptors in NAC and VTA – reinforcement
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Rats will injection heroin directly into NAC and VTA
150-300% increase in levels of DA in NAC while a rat pressed a
lever that delivered IV heroin
•Endogenous opioids are involved in the behavioral effects of natural reinforcers
•Naloxone (blocks opiate receptors) reduce the reinforcing effects of alcohol in
humans and rats
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OPIATES
 Neural Basis of Tolerance and Withdrawal
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•
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Antagonist-precipitated withdrawal – sudden withdrawal from longterm administration of a drug caused administration of an
antagonistic drug
Rats physically dependent on morphine and injected with
naloxone in brain
• Most sensitive sites: LC, PAG
• Amygdala - Weak withdrawal
LC
• Lesions reduce severity of antagonist-precipitated withdrawal
• Antagonist-precipitated withdrawal increases glutamate and
aspartate in LC
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STIMULANT DRUGS: COCAINE &
AMPHETAMINE
 Potent DA agonists, sites of action are different
 Cocaine deactivates DA transporters, blocks reuptake
 Freebase cocaine (crack) is smoked - enters brain very
quickly, very potent
•
Probably the most effective reinforcer of all available drugs
 Amphetamine stimulates release of DA
 Metamphetamine – related to amphetamine,
more potent
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STIMULANT DRUGS: COCAINE &
AMPHETAMINE
 If rats or monkeys are allowed to selfadminister cocaine, they often self-inject so
much cocaine that they die
 Rats that self-administer cocaine were almost
3 times more likely to die than were rats that
self-administered heroin
 IV injections of cocaine or amphetamine
increase DA in NAC
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STIMULANT DRUGS: COCAINE &
AMPHETAMINE
 Side effects of cocaine and amphetamine
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Psychotic behavior: hallucinations, delusions of
persecution, mood disturbances, repetitive behaviors
Symptoms resemble paranoid schizophrenia
•
Increased activity of DA is responsible for positive symptoms of
schizophrenia
 Long-term addicts
•
•
Decreased # of DA transporters, decreased number of
DA terminals
People may have increased risk of PD
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NICOTINE
 Accounts for more deaths than “hard” drugs
 Combination of nicotine and other chemicals in smoke is
carcinogenic – leads to cancer of the lung, mouth, throat,
esophagus
 World Health Organization (WHO)
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•
1/3 of people in the world smoke
50% of people who begin to smoke as adolescents and continue smoking
throughout their lives will die from smoke-related disease
 2015 – tobacco will be the largest single health problem
worldwide
 6.4 million deaths/year
 Deleterious effects on fetus (worse than cocaine?)
•
25% of pregnant women in US expose their fetuses to nicotine
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NICOTINE
 In humans - highly addictive
 In animals – highly addictive
 Nicotine stimulates nicotinic ACH receptors
 Increases activity of DA neurons of the mesolimbic
system and causes DA to be released in NAC
Injection of a nicotinic agonist into VTA will reinforce a conditioned
place preference (CPP)
• Injection of nicotinic antagonist into VTA will reduce the reinforcing
effect of iv injections of nicotine
Insula may be involved in smoking cessation.
•

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NICOTINE
 Endogenous cannabinoids play a role in reinforcing
effects of nicotine
•
Rimonabant - blocks CB1 receptors
• Reduces nicotine self-administration, by reducing release of DA in
NAC
•
•
Decreases reinforcing effects of nicotine
Help prevent relapse
 Withdrawal symptoms
•
Anxiety, restlessness, insomnia, inability to concentrate
 Overeating and weight gain
•
•
Nicotinic receptors are located on the terminals of GABAergic neurons in
LH that form synapses with MCH neurons
When nicotine activates these terminals, the release of GABA in
increased, which inhibits MCH neurons, suppressing appetite
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ALCOHOL
 Fetal Alcohol Syndrome (FAS) – one
of the leading causes of mental
retardation in the Western world
 Fetal development
•
Effects are most serious during last trimester and
several years after birth
 Exposure of the immature rat brain caused
widespread apoptosis
 Acts as a GABAa agonist, NMDA antagonist
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ALCOHOL
 Low doses
•
Mild euphoria and anxiolytic effect
 High doses
•
In-coordination and sedation
 Produces both positive (euphoria) and
negative reinforcement (anxiolytic)
 Increases activity of DA neurons in
mesolimbic system, increases release of DA
in NAC
•
DA release is related to positive reinforcement
•
DA antagonists reduce the euphoria produced by alcohol
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ALCOHOL
 Role on NMDA receptors
•
•
Due to blocking NMDA receptors, alcohol disrupts long
term potentiation (LTP)
May account for the deleterious effects of alcohol on
memory and other cognitive functions
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ALCOHOL
 Withdrawal
•
Decreases activity of mesolimbic neurons and their
release of DA in NAC
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•
If NMDA indirect antagonist is administered, DA secretion in
NAC recovers
Long-term suppression of NMDA receptors causes
upregulation (compensatory increase). When alcohol
stops, increased activity of NMDA receptors inhibits the
activity of VTA and release of DA in NAC
•
Can trigger seizures and convulsions, death
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ALCOHOL
 Role on GABAa receptors
•
Alcohol binds to one of many binding sites to increase
effectiveness of GABA in opening Cl- channel
• Anxiolytic effect
• Sedative effect
 Reinforcing effect of alcohol is partly caused by
its ability to trigger release of opioids
•
•
Opiate blockers (naloxone/naltrexone) block the reinforcing effects
of alcohol
Opioids play a role in cravings
• 1-3 weeks of abstinence increased the # of opiate receptors in
NAC
• Greater the # of receptors, more intense the craving
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CANNABIS
 THC – active ingredient in marijuana
 Site of action of endogenous cannabinoids in
brain is the CB1 receptor
•
Anandamide and 2-AG
 Administration of a drug that blocks CB1
abolishes the “high” produced by smoking
marijuana
 Injections of THC increase DA release in NAC
 Lab animals will self-administer CB1 agonists
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CANNABIS
 Mutation that blocks CB1 receptor production
•
•
Abolishes reinforcing effects of THC, morphine, heroin
Decreases reinforcing effects of alcohol and acquisition
of self-administration of cocaine
 Rimonabant – blocks CB1 receptors)
•
Decreases reinforcing effects of nicotine
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CANNABIS
 Hippocampus contains a high concentration of
THC receptors
 Marijuana affects memory
•
Impairs ability to keep track of a particular topic
 Drug disrupts normal functions of the
hippocampus
•
•
Endogenous cannabinoids facilitate activity of CA1 pyramidal cells
and LTP
Effects of exogenous cannabinoids disrupts spatial memory,
similar to hippocampal lesions
 Early cannabis use can increase your risk of
developing a psychotic illness later in life
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HEREDITY AND DRUG ABUSE
 Both genetic and environmental factors play a
role in determining a person’s likelihood of
consuming drugs and becoming dependent
•
•
Environment plays a stronger role in influencing a
person to try a drug (recreational)
Genetics play a stronger role in determining whether
the person becomes addicted
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THERAPY FOR DRUG ABUSE
 Treatment of Opiate Addiction

Most common treatment is methadone.




Potent opiate
Liquid - oral administration increases opiate level in brain
slowly, does not produce the same high (as injection of heroin)
Long-lasting, opiate receptors remain occupied, injection of
heroin has little effect – limited
Buprenorphine

Partial agonist for the μ opiate receptor




Drug has high affinity for receptor but activates it less than ligand
Reduces effects of ligand in regions of high concentration and
increases it in regions of low concentration
Blocks effects of opiates, produces weak opiate effect
Combination with naloxone
THERAPY FOR DRUG ABUSE
 Treatment of Cocaine Addiction
•
Immunotherapy
•
•
•
•
Conjugated cocaine to a foreign protein which stimulated rats’
immune system to develop antibodies to cocaine
Prevented cocaine from passing BBB, less sensitive to activating
effects of cocaine
Clinical studies underway (and with other drugs)
GABA agonist (gamma-vinyl GABA – GVG)
•
•
•
•
Decreased DA released in NAC after injecting a rat with cocaine
Baboons given GVG no longer learned a CPP for cocaine
GVG is not addictive, used to treat epilepsy
Clinical studies underway
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THERAPY FOR DRUG ABUSE
 Nicotine
•
•
•
•
Nicotine maintenance therapy
Rimonabant - CB1 antagonist
Bupropion – antidepressant drug, catecholine reuptake
inhibitor
Varenicline – partial agonist for the nicotinic receptor
 Alcohol
•
•
Naltrexone – opiate antagonist
Acamprosate – NMDA-receptor antagonist
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