1) Dopamine plays a key role in addiction by mediating pleasure, motivation, and salience, while genetic differences in dopamine receptors influence addiction risk. 2) Glutamate affects synaptic plasticity and long-term potentiation, which impact learning processes in addiction. 3) Stress responses differ in addicted individuals, and early-life stress can trigger addiction by sensitizing the brain's reward pathways.

1. Biological aspects of addiction
Kyle Smith
kylepatricksmith@gmail.com
Scaife Fellow Presentations
27 July 2012

2. Overview
Dopamine Glutamate Corticosteroids
Pleasure + Plasticity + Stress
Motivation Potentiation

3. Dopamine + Euphoria
• Conventional wisdom
says drugs give
hedonic pleasure,
promoting further use
– Mediated by
dopamine in striatal
regions
• Food, sex, and music
produce a like effect
– But drugs promote a
faster, stronger,
longer dopamine
release

4. D2 Receptors + Anhedonia
• Versus controls, addicted subjects were found to have
lower D2 receptor (D2R) expression and lower baseline
dopamine release
– These changes cause a blunted response to natural
rewards such as food and sex
– Drug-induced dopamine overcomes baseline deficiencies
Red=high D2R expression

5. Beyond Hedonic Pleasure
• Decreased striatal D2R has been associated
with decreased activity in inhibitory centers of
the brain (ACC, OFC, dorsolateral PFC)
– Associated with compulsive behaviors and
impulsivity
• Overexpression of D2R has been found to be
protective against drug addiction
– Non-addicts with a family history of addiction
have shown increased D2R in the striatum

6. Orbitofrontal Cortex + Motivation
• OFC participates
in decision-making
– Studies show
decreased glucose
metabolism in
OFC of addicted
subjects
– Also associated
with D2 receptor
availability

7. Dopamine + OFC metabolism

8. OFC + Motivation, cont.
• Dopamine increases
motivation, energizes
goal-seeking, and
informs cost-benefit
choices in OFC
• Drug paraphernalia and
related stimuli has been
shown to activate the
OFC in addicts
– “Beware people, places,
and things” D2R activation indicated by
decrease in availability

9. Incentive-Salience Model
• Hypermetabolism of OFC enhances saliency of
drug-induced cues
• Drugs are consumed not because they bring
pleasure, but because they are wanted
– Wanting does not equal enjoying

10. More on the OFC
• Changes to OFC impact the assessment of the
value of delayed gratification
– Causes preferential selection of immediate, small
rewards versus larger, delayed rewards
• Damage to OFC interferes with the elimination
of learned cravings for rewards that are no
longer pleasurable
– Even when drugs do not give reward, it is hard to
unlearn the desire for them

11. Glutamate + Learning
• Glutamate is an excitatory neurotransmitter
– Affects synaptic plasticity and long-term
potentiation (LTP) in dopaminergic cells
• Studies show that antagonism of glutamate
receptors AMPAR and NMDAR impair various
drug responses in mice
– Reduces lever pressing, place preference, stress-
induced relapse, and cue-induced relapse

12. Long-Term Potentiation
• In dopaminergic cells in the ventral tegmental
area (VTA), there is an upregulation of AMPAR
during drug-induced LTP
– Even a single exposure sensitizes the VTA to drug-
induced challenge

13. Long-Term Potentiation, cont.
• Two hypotheses:
– Increased AMPAR
responses induce
burst firing of
dopamine, as
opposed to low-level
tonic firing
– Excessive AMPAR
activation causes a
depolarization block,
reducing action
potential response to
ordinary stimuli

14. Stress + Addiction
• The limbic system, which
mediates addiction, is also
involved in the stress response
• In rats, stresses such as tail
pinch, social defeat, neonatal
isolation, electric footshocks,
novelty stress, and
immobilization have been
shown to increase drug
acquisition
• Rats and humans exposed to
stress have been shown to be
more sensitive to drug effects

15. Stress + Dopamine
• Evidence shows that in
early drug use,
glucocorticoids sensitize
the reward pathways
• Rats without adrenal
glands do not self-
administer cocaine
– When injected with
corticosteroids, they self-
administered cocaine in a
dose-dependent fashion

16. Hedonic Allostasis Model
• During addiction, elevated glucocorticoids create
an internal form of stress that resembles anxiety
• In hedonic allostasis model, downregulation of
reward pathways and upregulation of stress
factors creates negative affect in the patient
– Withdrawal symptoms, dysphoria, anxiety
• Relief from symptoms becomes primary factor in
drug use
– Users take drugs to “feel normal”

17. Genetics + the HPA axis
• Hypothalamic-pituitary-adrenal axis responses
to ethanol challenge have been shown to
predict future alcoholism
• Family history positive individuals have a
higher response to the Trier Social Stress Test

18. Stress Tests in Family-History Positive
vs. Negative Individuals

19. Genetic Variation in Stress Responses

20. Genetic Variation in Stress Responses

21. Early-Life Stress + HPA Axis
• Evidence suggests
some genetic
variations increase
development of
addiction only in
individuals who have
experienced significant
early-life stress
– Physical, emotional, or
sexual abuse or neglect

22. Early-Life Stress + HPA Axis
• These genetic variations can affect the HPA
axis, the dopamine reward pathway, and brain
morphometry
– PER1 circadian rhythm gene, KCNJ6 dopamine-
inhibiting potassium channel, SLC6A4 serotonin
transporter, BDNF affects brain shrinkage in
response to stress
– In rats, early-life stress has been shown to alter
opiate and GABA receptors

23. Conclusions
• Dopamine affects addiction through
mediation of reward, but also motivation and
salience
– Genetic differences in dopamine networks can be
predisposing or protective
• Glutamate affects synaptic plasticity and long-
term potentiation in addiction
• Stress responses differ in addicted and non-
addicted individuals
– Early-life stress can also trigger addiction