Drug Addiction & The Brain

According to a 2004 report, the WHO estimates

that over 200million people are addicted to
drugs.

Defining characteristic of drug addiction

Continued Compulsive & Out-of-Control drug use
despite serious negative consequences.
 Examples of Addiction
 Loss of Job & Home
 Loss of family
 Cirrhosis
 Depression
 Many addicts continue
despite such adverse
effects.
 The central question of addiction:

 What happens in the brain to cause an

addicted person to lose control of drug-taking
behavior despite such serious consequences?

 What neurophysiological changes are

associated with the addiction cycle?
 Common Drugs of Abuse
 Cocaine & Amphetamines
 Opiates
 Alcohol
 Cannabinoids
 Nicotine

 Each works by increasing the amount of

dopamine in the synapses of the
mesocorticolimbic dopamine system.
 Dopamine is Found in

Nigrostriatal

Mesolimbic

Mesocortical
 Cocaine
 Inhibits all 3 monoamine uptake transporters,
(dopamine, serotonin, and norepinephrine),
thereby increasing the amount of monoamines
in the synapse and potentiating monaminergic
transmission.
 Amphetamines
 Increases release of monoamines.

 Inhibits all 3 monoamine uptake transporters.

 Inhibits monoamine oxidase.

 Dopamine system appears to be the critical
substrate for the rewarding effects of cocaine &
amphetamines.

 All 3 dopamine receptor subtypes have been

implicated. D1, D2, D3
 Cocaine & Amphetamines

 Located in
Mesocorticolimbic
Dopamine system.
 Opiates
 Opioids activate
specific receptors
(µ, δ, & κ)
that couple with
G-proteins
 Opiates
Results in
1) inhibition of adenylyl
cyclase,
2) activation of inwardly
rectifying Potassium
channels,
3)inhibition of Calcium
channels.

Opiate receptors
mediate inhibitory
responses, & reduce
membrane excitability
 Opiates

 Opiate appear to
operate on the

 Ventral
Tegmental Area
 Inhibits GABA

 & The Nucleus

Accumbens
 Increases
dopamine
activity
 Alcohol
 At low doses of alcohol, dopamine is involved in
the rewarding effects of alcohol.

 Appears to modify the activity of serotonin

receptors, nicotinic receptors, & GABBA
receptors.

 Is believed to activate opioid peptide systems.

 Mice with blocked mu opioid receptors do not drink
alcohol.
 Alcohol

 The ventral
tegmental area

 The basal
forebrain
 Cannabinoids
 THC binds to G-protein-coupled cannabinoid-1
receptors.
 They are densely distributed in the
 Basal ganglia
 Cerebral-cortex regions
 Neural substrates
 The mesocorticolimbic dopamine system
 Increases the release of dopamine in the shell of
the nucleus accumbens
 Inhibits excitatory glutamatergic neurotransmission
in the substantia nigra.
 Nicotine
 Is a direct agonist at nicotinic acetylcholine receptors
which are widely dispersed throughout the brain.

 Nicotinic receptors implicated in reinforcing effects of

nicotine are localized in the mesocorticolimbic
dopamine system.

 Increases dopamine neurotransmission & energy

metabolism in the nucleus accumbens.

 Also appears to influence opioid peptide systems.

 First use is for pleasure, but subsequent usage
becomes compulsive.

 Long term use of drugs causes

neurophysiological adaptations and disrupts
reward system

 Tolerance, Sensitization, & Withdrawal

 Tolerance
 Leads to modifications of drug use to obtain
desired effects, by increasing the dose, or
increasing the frequency of use or both.

 The increased drug use causes deregulations in

the reward system as the brain adapts to the
over stimulation induced by drug use.
 Tolerance
 Some people are able to maintain the same initial
dosage by spacing out their usage. However, drug
dependence develops when they begin using them
more frequently so that tolerance begins to develop.

 In one experiment ex-addict volunteers were allowed

to self-administer heroin or morphine. Eventually, the
maximum permissible doses were taken. One guy
escalated is dose ten thousand times what was initially
effective and he still demanded more.
 Metabolic Tolerance
 The body (primarily the liver) adapts by getting better
at destroying the drug
 Each repetition of the initial dose provides less drug
for shorter and shorter times at the sites of action in
the brain; so progressively higher doses are needed
(Goldstein, 2001).
 Example: Pentobarbital, a short-acting barbiturate

used as a sleeping pill. An initial dose is sufficient

to cause sleep and remains in the blood for a few
hours. But with repeated dosage, the drug is
destroyed mor and more reapidly and thus becomes
less effective.
 (Goldstein, 2001).
 Cellular Tolerance
 Neurons adapt to the drug becoming less
sensitive to it with continued exposure.
 The underlying neurochemical adaptation is masked
by the apparent normality of brain function. But these
adaptations become apparent when the drug is
withdrawn.

 (Goldstein, 2001).
 Tolerance Example: Opiates
 Opioid
tolerance:
Prolonged use
decreases the
number of opioid
receptors and
desensitizes
them, and can
lead to their
being
internalized by
the neuron.
(Figure from Stahl, 2002)
Tolerance
 Sensitization
 The opposite of tolerance: brain becomes more
sensitive to effects of drug.
 May act to increase the incentive salience of the drug
and thereby contribute to compulsive drug use.
 Increases craving and vulnerability to relapse even
after years of successful detoxification.

 Usually seen with stimulants, opioids, and nicotine.

 Brain microdialysis studies have shown an increase in

transmitter release to a standard dose of drug. (Nutt, 1997)
 Sensitization is associated with
 Alterations in the
mesocorticolimbic
dopamine system,
 Particularly in
glutamate &
dopamine
transmission in the
nucleus accumbens.
 Elevated levels of
glutamate receptors
 Long-lasting
alterations in patterns
of gene expression in
the terminal
mesolimbic dopamine
systems.
 Sensitization
 Repeated use of cocaine & amphetamine
increases the number of dendritic branch points
& spines on neurons in the nucleus accumbens
and medial prefrontal cortex.
 Withdrawal
 Results from the neurochemical adaptations in the
brain associated with tolerance, and is observed when
the drug is removed. (Goldstein, 2001)

 The symptoms of withdrawal are usually opposite of

the effects of the drug. (Goldstein, 2001)

 Compels addicts to resume drug use to prevent or

reduce physical symptoms and dysphoria. (Cami & Farre, 2003)
 Withdrawal: Opiates
 Chronic activation of opioid receptors produces effects
opposite to those of acute activation.
 It upregulates cyclic adenosine monophosphate
(cAMP) signaling pathways.

 Tolerance to the inhibitory effects of the opioids

occurs in the locus ceruleus.
 The locus ceruleus regulates arousal, stress
responses, and the autonomic nervous system.
 When opiate levels fall, there is an increase in activity
in the locus ceruleus. Without the inhibitory effects of
opiates, the locus ceruleus becomes over active.
 Withdrawal
 The over activity of the locus ceruleus is
associated with the severe dysphoria associated
with opiate withdrawal.

 The intense feelings of dysphoria that is

associated with withdrawal often serve as
motivation to continue drug use.

 Continuing drug use is negatively reinforcing in

that it removes the unpleasant effects of
withdrawal.
 Stress Systems
 Drug use & withdrawal
activate peripheral &
central stress systems.

 Short-term use
elevates glucocorticoid
levels & CRF levels.
(Camil & Farre, 2003)
 Stress Systems
 These hormonal
elevations have been
related to the rewarding
properties of drug use.

 During withdrawal, an
increase in CRF in the
amygdala has been
related to stress & the
negative effects of
abstinence
(Camil & Farre, 2003)
 Homeostasis
 Homeostatic adaptations can be understood as
compensatory responses of cells or circuits to
excessive stimulation due to chronic drug
intake.

 These adaptations tend to dampen drug effects

and produce tolerance and withdrawal.

 Are reversible: with extended abstinence, the

homeostatic adaptations dissipate.
 Homeostasis
 Homeostatic mechanisms cannot account for
addict’s tendency to relapse long after
withdrawal symptoms have disappeared.

 Relapse often occurs upon exposure to

situational cues associated with drug use.

 Thus part of the addiction process involves

associative learning.
 Neuroimaging & The Frontal Cortex
 Recent neuroimaging studies have implicated
the frontal cortex in addiction.

 Loss in volume of the frontal lobe has been

associated with drug addiction.

 Cocaine abuse results in morphological changes

in dendrites & dendritic spines in the prefrontal
cortex & the nucleus accumbens.
 The Frontal Cortex & Intoxication
 Prefrontal cortex &
anterior cingulate gyrus
are active during
intoxication.

 Activation in those areas

is also associated with the
subjective experience of
intoxication & its
reinforcing effects.
 The Frontal Cortex & Craving
Cocaine abusers exposed to
a video depicting drug-
related stimuli exhibited
greater activation in the
pre-frontal and anterior
cingulate.

(Figure from Goldstein & Volkow, 2002)

The Frontal Cortex & Learning in Addiction
 Alterations in the frontal cortex may be
involved in learning new addictive behaviors.

 One of the functions of the frontal cortex is to

regulate goal-oriented behavior.

 The over activation of dopamine in the frontal

cortex areas, as a result of drug abuse, alters
the frontal cortex’s ability to regulate goal-
oriented behavior.
The Frontal Cortex & Learning in Addiction
 The result is an overvaluing of drug reinforcers
& an undervaluing of alternative reinforcers.

 This shift in value of reinforcers contributes to

deficits in inhibitory control & compulsive drug
abuse.
Expectation & Brain Function in Drug Abuse
 Reinforcing effects of drugs represent a
complex interaction between pharmacological
effects and conditioned responses.

 Expectation enhances the regional brain

metabolic & reinforcing effects of stimulants in
cocaine abusers.

 Expectation enhances pharmacological effects

of stimulants by amplifying dopamine &
norepinephrine signals by blocking their
transporters.
Expectation & Brain Function in Drug Abuse
 Vulnerability to Addiction
 Personality Factors
 Risk-taking or novelty seeking traits
 Psychiatric disorders

 Genetic Factors
 Children of alcoholic parents were more likely to
develop alcoholism even when adopted and raised
by non-alcoholic parents.
 Vulnerability to Addiction
 Environmental Factors Can alter the reinforcing
effects of drugs, particularly cocaine.
 Drug availability
 Availability of alternative reinforcers
 Living in an enriched environment
 Social status
 Vulnerability to Addiction
Social Dominance in monkeys can influence the
Rewarding effects of cocaine.

 Morgan & colleagues (2002) used PET imaging

to study dopanergic activity & measured the
amount of cocaine self-administration in
monkeys.
D2 receptors increase in dominant monkeys.
(Morgan et al., 2002)
Subordinate monkeys self-administered more cocaine
(Morgan et al., 2002)