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Neurobiology of drug action and
addiction
Richard Palmiter
Dept Biochemistry
The dopamine reward system
Prefrontal cortex
Hippocampus
Striatum
Nucleus accumbens
Substantia nigra
Ventral tegmental area
Wise (2002) Neuron
Some dopamine circuit details
D1R
GABAAR
D2R
DA
GABAAR
NAc
GABA
VTA
Drugs release dopamine
DA
Cocaine, amphetamine
Morphine, heroin, nicotine
D1R
D2R
NAc
Ethanol ?
DA
VTA
Animals like drugs that release dopamine
self administration
Animals like dopamine
self stimulation
DA
Glu
D1R
D2R
NAc
Medial forebrain
bundle (MFB) passes
through lateral
hypothalamus
DA
VTA
Dopamine help animals learn where
important (salient) things happen
Animals like the effects of drugs
Conditioned place preference
drug
Animals learn to like the place where they
experience the effects of drugs
Drugs usurp to dopamine system
Drugs have greatest effect when
given in a novel environment
Voluntary drug administration is more
addictive than involuntary administration
Voluntary drug
administration
Involuntary drug
administration
‘yoked situation’
Chronic drug exposure
changes the brain
Imagining
the brain on
drugs
Is reduced D2R
availability due
to less receptor
or more DA?
Volkow (2004) Nat Rev.
Distal spines
Medium spiny neuron morphology in NAc changes
Robinson, TE (2004)
amphetamine
Drugs produce stable
changes in the brain
cortex
What are these changes and
do they explain addiction?
Glu
Glu
D1R
Glu
glial
cells
DA
D2R
NAc
Glu R
•Morphological
•Receptors
•Signaling pathways
•[Glutamate]
DA
VTA
locomotion
Drug-induced changes produce sensitization
days
PBS
1
2 3 4
25
Drug
Sensitization reflects stable changes
Cross -sensitization
Presumably, when some of those
drug-induced changes become
large enough or persistent enough
the associations between state
and place become habitual
Which changes are addictive??
Are they reversible?
Bodily state influences drug-taking activity
self administration
Lever presses
Hungry (stressed)
animals will lever press
more for drugs or
electrical stimulation
than fed animals
How does stress enhance responding?
fed fasted
Lever presses
Reinstatement of drug taking activity
extinction
training
drug
self administration
reinstatment
saline
self administration
•Cue
•Stress
•Drug (i.v)
cue
What happens during reinstatement?
Memories (associations) are recalled
•Long-term memories require protein synthesis
•Memories become labile when recalled
•Restoring memories requires protein synthesis
again !!
Could bad associations be removed
by blocking protein synthesis during
recall (reinstatement)??
Conditioned place preference for morphine
removed by blocking protein synthesis after recall
Alberini (2006) JN
Problems with the VTA-dopamine
hypothesis of addiction
• Dopamine agonists are not addictive
• Some drugs that release dopamine are not
addictive
• Some aspects of reward learning are
intact in mice lacking dopamine
• Mice with dopamine signaling restored to
dorsal striatum (not NAc) show normal
appetitive behaviors
• Other neurotransmitters are involved
Drugs release dopamine, but…
DA
D1R
D2R
NAc
Cocaine, amphetamine
Morphine, heroin, nicotine
DA
VTA
Dopamine receptor agonists are not drugs
Is dopamine action in nucleus
accumbens critical for the
pleasurable effects of drugs and
drug/place association ?
Conditioned place preference
drug
Animals learn to like the place where they
experience the effects of drugs
Mice without DA
can learn CPP for
morphine & cocaine
Mice without the
cocaine receptor
(DAT) can learn CPP
for cocaine
Hnasko (2005,2007) Nature, JN; Jones (2005) PNAS
Serotonin
Other neuromodulators are also required
Conditioned place preference
drug
Mice without
norepinephrine
do not learn CPP
for morphine
Animals learn to like the place where they
experience the effects of drugs
Olson (2006) Science
Mice lacking mGlu5 do not show cocaine CPP
Lever presses
Drug taking does not necessarily
lead to addiction
extinction
training
3 months
drug
reinstatment
self administration
saline
self administration
•Cue
•Stress
•Drug (i.v)
cue
Deroche-Gamonet..Piazza, 2004 Science
Hallmarks of Addiction
i. Subject has difficulty limiting drug intake
persistence
ii. Subject has high motivation to take drug
motivation
i. Subject continues to take drug despite
adverse consequences
resistance
Many days of self administration, 5 days
withdrawal, reinstatement with cocaine, then
divide into groups based on response
40% lowest
persistence
40% highest
resistance
motivation
Piazza (2004)
Many days of self administration, 30 days
withdrawal, reinstatement with cocaine or cue
40% lowest
very low doses
40% highest
cue
Piazza (2004)
56 rats trained for a long time at self
administration
Three tests: persistence, resistance, motivation
Consider rats ranking in top 1/3rd of group
on each test: thus, individual rat could get
score of 0, 1, 2 or 3
Piazza (2004)
Conclusions:
Rat addiction as described here is:
•Requires long self-administration paradigm
•Independent of amount of cocaine delivered
during training
•Independent of motor activity
•Vulnerability is function of individual
What are those individual differences???