Addiction:
Transition from Molecular to
Behavioral Understanding
John Neumaier, M.D., Ph.D.
Department of Psychiatry
Harborview Medical Center
and
University of Washington
Goals
– How does a psychiatrist think about
addiction?
– Review some psychological and learning
aspects of addiction theories
– Review some molecular events associated
with addiction
– Consider the substrates of enduring
addiction and risk for relapse
Impaired Response Inhibition and
Salience Attribution
Goldstein and Volkow (2002) Am J Psychiatry 159:1642
Rostral Anterior Cingulate Cortex activation
in Stroop task (tests executive function)
Bolla et al. (2004) J Neuropsychiatry Clin Neurosci 16:456.
What are the psychological
aspects of addiction?
– Emotional (liking)
– Motivational (wanting)
– Learning (cognitive and associative)
Robinson and Berridge (2003) Annu Rev Psychol 54:25-53.
Wanting
• Motivation to obtain a reward (such as a
drug)
– Can be independent of “liking” the reward
• Pathological wanting = craving
• The importance of the reward grows with
repeated exposure (sensitization)
• Can be inferred by how hard someone will
work to obtain the reward
Learning
dorsolateral
Sensory, insular ctx inputs
S/R associations
Sensorimotor?
dorsomedial
PFC inputs
S/R associations
Limbic?
Molecular adaptations associated
with addiction are likely to be
stage specific
– Sensitization
– Tolerance
– Escalation
– Withdrawal
– Extinction
– Relapse
sensitization
tolerance
What are the neural plasticity events
associated with these adaptations?
“Incubation” of craving
Yavin Shaham
What are the effects of social
stress on drug
self administration?
Stress Induced Reinstatement
Shalev et al (2002) Pharmacol Rev 54:1-42.
Escalation
What might pharmacological
treatments for addiction look like?
•
•
•
•
•
•
Prevent initial drug events?
Shift balance of + and - features?
Prevent reinstatement?
Facilitate extinction learning?
Deconstruct reconsolidation of memory?
Shift from out of control to regulated
use?
Serotonin and Reward
SEROTONIN RECEPTOR SEQUENCE HOMOLOGY
• Many different
receptors implicated
• 5-HT1B and 5-HT6
have roughly
opposing effects
5-HT
5-HT2A
2A
5-HT
5-HT2C
2C
5-HT
5-HT2B
2B
Gq
Gq
5-HT
5-HT1A
1A
5-HT
5-HT1B
1B
5-HT
5-HT1D
1D
5-HT
5-HT1E
1E
5-HT
5-HT1F
1F
Gi
Gi
5-HT
5-HT5A
5A
5-HT
5-HT5B
5B
?
?
5-HT
5-HT77
Gs
Gs
5-HT
5-HT66
Gs
Gs
Andrews and Lucki Psychopharm. (2001) 155:221–229
Neumaier et al (2002) J Neurosci 22:10856.
EtOH consumed (g/kg)
4
3.5
*
3
2.5
2
1.5
1
.5
0
1B
Hoplight et al (2006) Alcohol 38:73.
GFP
UNH
5-HT1B & “Binge Cocaine”
• 3 weeks of noncontingent cocaine injections
– 15 mg/kg ip every hour X 3 injections daily
•
•
•
•
or 1 day of 3 cocaine injections
Saline controls
Unhandled cage controls
5-HT1B mRNA by ISHH
Hoplight et al (2006) Neuropharmacol
Hoplight et al (2006) Neuropharmacol
Study Design
Guide cannula
Gene transfer Behavioral testing
Food restriction
sacrifice
Mitchell et al (2007) Neuropsychopharm EPub
Operant Conditioning
• 1st session
– 10 sucrose pellets presented
noncontingently
– 50 trials of stimulus cue light with lever
presentation, response within 10 sec
rewarded with sucrose pellet
• 2nd and 3rd session, same except 3
noncontingent sucrose pellets
% successful trials
60%
40%
*
20%
0%
no surgery
day 1
sham
GFP-only 5-HT6/GFP
day 2
day 3
Mitchell et al (2007) Neuropsychopharm EPub
Is learning deficit due to
increased 5-HT6 activity?
• SB258585 (5 mg/kg ip)
or saline vehicle
immediately before 1st
and 2nd sessions
80%
% successful trials
• SB258585 or BGC20761 given immediately
after 2nd day session
had no effect
60%
40%
*
20%
0%
GFP-only 5-HT6/GFP GFP-only 5-HT6/GFP
saline
day 1
+ SB258585
day 2
day 3
Is effect of 5-HT6 receptor
overexpression subregion specific?
80%
% successful trials
60%
40%
*
20%
0%
GFP-only
5-HT6/GFP
GFP-only
dorsomedial
day 1
Voorn et al TINS (2004) 27:468
5-HT6/GFP
dorsocentral
day 2
day 3
5-HT6 overexpression in NAcc shell
• No significant effects on locomotor
sensitization
• Conditioned place preference, compared
HA6/GFP to GFP injected animals
Conditioned place preference to cocaine (20 mg/kg)
900
450
0
5-HT6 antagonist & cocaine reward
• Ro4368554 or vehicle given before
subthreshold doses of cocaine (5 mg/kg)
*
Ferguson et al 2007 Biol Psych in press.
Implications
Glu
• Impaired… or stable?
5-HT
• Dopamine and Serotonin
striatum
- opposing factors?
5-HT6
• 5-HT6 receptors and ACh
GABA
ACh
DA