Chapter 18
Drug Abuse
Background
• Humans discovered long ago that many substances in nature (e.g.
plants materials) had medicinal qualities
– Some of these also served as “recreational” drugs, or substances that
produced pleasing effects (most notable example is alcohol)
Addictive drugs
Drug
Sites of Action
Ethyl alcohol
NMDA receptor ANT; GABAA receptor ANT
Barbiturates
GABAA receptor AGO
Benzodiazepines
(tranquil)
GABAA receptor AGO
Cannabis
CB1 cannabinoid receptor AGO
Nicotine
Nicotinic Ach receptor AGO
Opiates
 and  receptor AGO
PCP and ketamine
NMDA receptor ANT
Cocaine
Blocks reuptake of DA, 5-HT and NE
Amphetamine
Causes release of DA
Physical vs Psychological Addiction
• Many people believe that “true” addiction is caused by the unpleasant
side effects that occur when an addict tries to stop taking the drug
• Physical dependence vs. psychic dependence
• Heroin addiction considered prototype for all drug addictions:
– Heroin addicts become physically dependent on the drug
– Tolerance – decreased sensitivity to a drug that comes from its continued
use
– Withdrawal – the appearance of symptoms opposite to those produced by
a drug when the drug is no longer taken
• Tolerance may be produced by the body’s attempt to compensate for
the unusual condition of heroin intoxication, thus when the addict stops
taking the drug, the compensatory mechanisms will become apparent
• However, tolerance and withdrawal do not occur immediately,
something else must be happening in order to get the addict to start
taking the drug in the first place (i.e. reinforcing effects)
Positive reinforcement
• Drugs that lad to dependency must first reinforce people’s behavior
• Positive reinforcement refers to the effect that certain stimuli have on
the behaviors that preceded them
• Addictive drugs have reinforcing effects
– i.e. their effects include activation of the reinforcement mechanism
• Role in drug abuse
– The effectiveness of a reinforcing stimulus is greatest if it occurs
immediately after a response occurs
– This phenomenon explains why the most addictive drugs are those that
have immediate effects
• e.g. heroin is preferred over morphine because it has a more rapid effect
– The immediate reinforcing effects of a addictive drug can overpower the
recognition of the long-term aversive effects
Positive reinforcement
• Neural mechanisms
– All natural reinforcers cause the release of DA in the nucleus accumbens
– Addictive drugs (including amphetamine, cocaine, opiates, nicotine,
alcohol, PCP, and cannabis) trigger the release of DA in the NA
• Some do this by increasing te activity of DA neurons in mesolimbic system
• Some inhibit reuptake of DA by terminal buttons
Negative reinforcement
• A behavior that stops or reduces and aversive stimulus will be
reinforced. This phenomenon is called negative reinforcment
• Do not confuse negative reinforcement with punishment
– For neg. reinforcement – the response must make an aversive stimulus
stop
– For punishment – the response must make the aversive stimulus occur
• Reduction of withdrawal effects (by taking the drug again) serve as
negative reinforcement
• Could also explain why a person starts taking a drug in the first place
– Drug effects may help relieve bad feelings that person may be having (e.g.
drink when feeling upset)
Cravings and relapse
• When an addictive drug activates the mesolimbic DA system, it gives
“incentive salience” to stimuli present at that time
– i.e. stimuli associated with taking that drug become exciting and
motivating
• When a person with a history of drug abuse sees or thinks about these
stimuli they experience a craving, or an impulsion to take the drug
• Small doses of the drug can also elicit cravings
• Reinstatement model of drug seeking in lab animals
– First trained to make a response that is reinforced by IV injection of drug
(e.g. cocaine)
– Next, response is extinguished by only injecting saline after response
– Once animal has stopped responding, a “free” injection will be
administered, and the animal will begin to respond again
– This relapse involves activation of the mesolimbic DA system
Cravings and relapse
• Long-term drug abuse in both humans and lab animals produces longterm changes in the brain
• Imaging studies show increase in activity in orbitofrontal cortex and
anterior cingulate cortex when taking or craving an addictive drug
– Decrease in activity during withdrawal
• NMDA-receptor-dependent LTP and LTD can take place in NA and
VTA of mesolimbic system
• Other stimuli can also trigger relapse
– e.g. stressful situations can cause former drug users to relapse
– However, social “satisfaction” produces less need of artifical reward via
drugs
– Drug craving elicited by stress depends on the secretion of CRH (i.e. if
CRH is not secreted, then relapse will not occur)
Opiates
• Opium is derived from resin produced by the opium poppy, and has
been eaten and smoked for centuries
• Opiate use (usually heroin) is illegal in most countries, produces
tolerance, addicts may often use unsanitary needles, and pregnant
women taking the drug will pass on addiction to fetus
• Opiates (endogenous opioids) are secreted when an animal is
performing behaviors that are important to its survival
• Neural basis of reinforcing effects
– Lab animals will self-administer opiates
– When an opiate is administered it stimulates opiate receptors located on
neurons in various parts of the brain and produces analgesia, hypothermia,
sedation, and reinforcement
– μ and δ receptors responsible for analgesic effects; κ produces aversive
effects (e.g. dynorphin – endogenous ligand for κ opiate receptor)
Opiates
• Neural basis of reinforcing effects
– Opiate injection caused increased release of DA in NA
– The reinforcing effects of opiates are produced by activation of neurons of
the mesolimbic system and release of DA in the NA
– However, opiates can reinforce behavior independent of their effects on
the mesolimbic DA system
– Animals with lesions of NA still have behavior reinforced with opiates
• Tested with conditioned place preference, which is the learned preference for
one location over another in which an organism encountered a reinforcing
stimulus
• CPP still occurs with opiates even after destruction of NA
• Neural basis of withdrawal effects
– Periaqueductal gray (PAG), locus coeruleus, and amygdala
– Antagonist-precipitated withdrawal – sudden withdrawal from long-term
admin of a drug caused by cessation of the drug and admin of an
antagonistic drug (e.g. naloxone for opiates); most sensitive site was locus
coeruleus
Opiates
• Neural basis of withdrawal effects
– Intracellular process involved in development of withdrawal symptos to
opiates involves a protein called CREB (cyclic AMP-responsive elementbinding protein)
– Long-term exposure to opiates causes tolerance, or a decreased sensitivity
of neurons to opiates
– This decreased sensitivity (i.e. downregulation) occurs even though the
number of opiate receptors does not change, suggesting some type of
intracellular alteration
– CREB plays a critical role in the intracellular events responsible for the
withdrawal effects of opioids
– CRH is involved in craving caused by stress for opiates
Cocaine and Amphetamine
• Have similar behavioral effects, because both act as potent DA
agonists
• Cocaine binds with and deactivates the DA transpoter proteins, thus
blocking reuptake
• Amphetamine directly stimulates the release of DA from terminal
buttons
• Excitatory behavioral effects (e.g. euphoria, feelings of power,
talkative)
• Animals will self-admin
• Also see psychotic behavioral effects (e.g. hallucinations, delusions of
persecution, mood disturbances, and repetitive behaviors) that very
closely resemble schizophrenia
• May have adverse long-term effects on brain
– Decrease in number of DA transporters
Cocaine and Amphetamine
• Activate mesolimbic DA system and reinforce drug-taking behavior
• IV injection of both increase concentration of DA in NA
• NA is critical site for the reinforcing effects of cocaine and
amphetamine
• Neurons in the NA participate in the reinforcing effects of cocaine,
with groups of neurons participating in triggering behavioral response,
reinforcing effects, and cravings
• Long-term use does not produce tolerance, and may even produce
sensitization; withdrawal symptoms are not physical, but can still be
unpleasant, such as dysphoria or decreased ability to experience
pleasure
Nicotine
• The combination of nicotine and other sustances in tobacco smoke is
carcinogenic and leads to cancer of the lungs, mouth, throat and
esophagus
• 1/3 of adult population of the world smokes, even when aware of
averse health effects
• Lab animals will also self-admin
• Stimulates ACh receptors, and increases activity of DA neurons of
mesolimbic system and causes DA to be released in NA
• Injection of nicotinic agonist directly into VTA will produce a CPP
• Injection of nicotinic antagonist into the VTA will reduce the
reinforcing effects of IV injections of nicotine
• Reinforcing effect of nicotine occurs in VTA, but not NA
• Some of the reinforcing effects of tobacco smoke may be mediated by
nicotinic ACh receptors located outside CNS
Nicotine
• The nicotinic ACh receptor exists in 3 states:
– When a burst of ACh is released by terminal button, the receptors open
briefly, permitting Ca+ to enter
– Within milliseconds, AChE has destroyed ACh and receptors either close
again or enter a desensitized state, during which they do not react to ACh
– However, when a person smokes, the level of nicotine in the brain raises
slowly and stays steady for a prolonged period of time because it is not
destroyed by AChE
– Thus nicotine has dual effects on nicotinic receptors: activation and then
desensitization
• The first dose of nicotine in the morning brings the most pleasure,
because the period of abstinence during the night has allowed many of
their receptors to enter the closed state and become sensitized again
• Cravings in long-term caused by LTP in the VTA
• Cessation causes withdrawal symptoms (e.g. anxiety, restlessness,
insomnia, and inability to concentrate)
Alcohol and Barbiturates
• Alcohol has greater costs to society than any other drug
• Has the most serious effects on fetal development during the brain
growth spurt period, which occurs during the last trimester of
pregnancy and for several years after birth
• Alcohol has 2 primary sites of action:
– Serves as an indirect agonist at GABAA receptors
– Indirect antagonist at NMDA receptors
• Both of these actions trigger apoptosis
• Exposure to alcohol later in life may also produce long-lasting changes
in susceptibility to addiction
• At low doses, alcohol produces mild euphoria and has an anxiolytic
effect; at higher doses it produces incoordination and sedation; also
removes the inhibitory effect of social controls on behavior
Alcohol and Barbiturates
• Produces both positive (euphoria) and negative (anxiolytic)
reinforcement
• Unique combination of both positive and negative effects that makes
alcohol so reinforcing
• Lab animals can be induced to become dependent on alcohol
– Most animals find the taste of alcohol to be aversive
– However, can add supplements to alcohol to get them to consume it
• e.g. sucrose, beer, gelatin (Rowland et al. 2005)
• Increases activity of DA neurons in mesolimbic system and increases
release of DA in NA
• The perceptual effects of alcohol are mimicked by both GABA
agonists and NMDA antagonists
– Drug discrimination procedure – an experimental procedure in which an
animal shows, through instrumental conditioning, whether the perceived
effects of two drugs are similar
Alcohol and Barbiturates
• Like alcohol, NMDA antagonists produce sedative, hypnotic, and
anxiolytic effects and interfere with cognitive performance
• Alcohol also disrupts LTP and interferes with spatial receptive fields of
place cells in the hippocampus
• Withdrawal from alcohol intake decreases activity of mesolimbic
neurons and their release of DA in the NA; can also cause seizures that
may be mediated by activation of NMDA receptors
– These seizures can be blocked by NMDA receptor antagonists
• The sedative effect of alcohol appears to be mediated by the GABAA
receptor
• Barbiturates have similar effects to alcohol; however, binding sites
appear to be different
Cannabis
• THC, active ingredient in marijuana, activates endogenous
cannabinoid receptors
• Has a stimulating effect on DA neurons in NA
• Appears to act directly on DA terminal buttons
• Many lab animals will self-admin drugs that stimulate CB1 receptors
• A targeted mutation that blocks production of CB1 receptors abolishes
the reinforcing effects of cannabinoids, morphine and heroin
• The hippocampus contains a large concentration of THC receptors
• Marijuana affects memory: it impairs ability to keep track of a
particular topic, etc.
• Excessive activation of CB1 receptors in field CA1 appears to interfere
with normal functioning of the hippocampus
• Long-term effects of marijuana include bronchitis, increased risk for
lung cancer, minor impairments of memory and attention
Heredity and drug abuse
• Not everyone is equally likely to become addicted to a drug
• 2 possible sources of individual differences: heredity and environment
• Most research of effects of heredity on addiction have been devoted to
alcoholism
• Alcohol consumption is not distributed equally across the population
• Heredity appears to be more important than environment
• 2 types of alcoholics: “steady drinkers” – those you cannot abstain but
drink consistently; and “bingers” – those who go without for long
periods of tie, but unable to control themselves when they start
• Steady drinking strongly influenced by heredity, binge drinking by
both heredity and environment
• Personality differences that may lead to alcoholism may be due to
differences in the sensitivity of neural mechanisms involved in
reinforcement, exploration and punishment
• Also may involve differences in DA mechanisms
Animal models and drug abuse
• Several different strains of alcohol preferring rats have been bred
• P rats (alcohol preferring) vs NP rats (non-alcohol preferring)
– When given alcohol for first time, both groups show no preference
– However, after a short time of exposure to alcohol soltuion in addition to
water, P rats will show a greatly increased preference for alcohol solution
during next test
• Found lowered levels of DA in NA of P rats
• A low level of DA in NA correlates with ahedonia and dysphoria, and
some forms of alcoholism may be caused by decreased sensitivity to
reinforcement
Therapy for drug abuse
• Most common treatment for opiate addiction is methadone
maintenance
– Methadone is a potent opiate, which is administered by clinics in liquid
form, and does not produce a high, since the rate of admin is slow
• Opiate antagonist, such as naloxone, are used by hospitals for
treatment of heroin overdose
• Several treatments for nicotine addiction:
– Gum, patch, etc.: all methods maintain sufficiently high level of nicotine
in brain to decreases cravings; once smoking habit is gone, the dose can be
lowered to wean them off
• 5-HT agonists can help with alcoholism, also NMDA receptor
antagonists