Reconsolidation, Cocaine and

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Reconsolidation, Cocaine and Matrix
Metalloproteinases
Barbara A. Sorg Washington State University
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Addiction is Learned
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Enzyme MMP

Collagenases MMPs-1, 8, 13, 18 Gelatinases MM
Ps-2, 9 Stromelysins MMPs-3, 10,
11 Membrane-type MMPs 14-17, 24, 25 (
MT1-6 MMPs) Others (Matrilysins MMP-7,
26 Metalloelastase MMP-12
4
post
NMDA R
glutamate
pre
ECM Molecules
5
post
NMDA R
pre
Active MMP
ECM Molecules
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MMP inhibition with FN-439 impairs water maze
performance
Meighan et al. J. Neurochem. (In Press)
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Does MMP inhibition prevent acquisition
or consolidation of cocaine-induced CPP?
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MMP inhibition attenuates acquisition
consolidation of CPP
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Does MMP inhibition prevent reconsolidation?
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MMP inhibition disrupts reconsolidation of CPP
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Activity
aCSF
FN-439
100
75
Photocell counts per min spent on cocaine-paired
side
50
25
0
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Repeated exposure to MMP inhibitor in context
only does not alter reinstatement of CPP
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Conclusion
Both the context AND cocaine are required to
disrupt reconsolidation of the cocaine memory by
the MMP inhibitor.
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Cocaine-Primed Reinstatement Increases MMP-3
mRNA in Amygdala
Cocaine Prime
Saline Prime
MMP-3
GAPDH
3 hr
Amygdala
300
250

200
MMP-3 mRNA ( Saline)
150
100
50
0
3 hr
1 hr
Time After Cocaine-Primed Reinstatement
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Summary of reconsolidation studies as applied
to drug abuse
Pharmacological agents can be used to

• Disrupt the conditioned reward value of the CS
  (light) (Pavlovian to instrumental transfer, in
  absence of drug) Lee et al. (2005) Neuron
  47795.

• Disrupt the drug-associated contextual memory
• (in absence of drug)
• also, Miller and Marshall (2005) Neuron 47873.

• Disrupt the drug-associated contextual memory
• (in presence of drug)

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Questions/Challenges Ahead

• Does disruption of reconsolidation reduce
  craving (in addition to expression of
  cocaine-seeking behavior)?

• Is the memory impairment from disruption of
  reconsolidation long-lasting, or will
  maintenance treatments be required?

• If the memory is partially present after
  disruption of reconsolidation, does relapse to
  drug-taking cause reconsolidation and therefore
  strengthening of the memory?

• Does extinction alter (facilitate or impair)
  reconsolidation
• of a drug memory?

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?
Collaborators Drs. Joseph Harding Jay Wright
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Use almost can change the stamp of nature
Hamlet
Can disruption of reconsolidation change the
stamp of drugs?
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Examples of stimuli affecting brain MMPs
MMP Brain structure
Up/downregulation
MMP-2 Hippocampus Seizures, transient
ischemia traumatic brain injury MMP-3 Corte
x transient ischemia, traumatic brain
injury MMP-9 Hippocampus Spatial
learning, Sleep deprivation, Alzheimers
disease MMP-9 Cortex Spatial learning,
transient ischemia