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Reconsolidation, Cocaine and Matrix Metalloproteinases Barbara A. Sorg Washington State University.

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Presentation on theme: "Reconsolidation, Cocaine and Matrix Metalloproteinases Barbara A. Sorg Washington State University."— Presentation transcript:

1 Reconsolidation, Cocaine and Matrix Metalloproteinases Barbara A. Sorg Washington State University

2 Addiction is Learned First Drug Use Repeated Drug Use Consolidation Drug/Drug Cue (Reinstatement) Recall/Reactivation Addiction Process Matrix Metalloproteinases (MMPs) Synaptic Remodeling Learning Memory Process Reconsolidation

3 Enzyme MMP CollagenasesMMPs-1, 8, 13, 18 GelatinasesMMPs-2, 9 StromelysinsMMPs-3, 10, 11 Membrane-typeMMPs 14-17, 24, 25 (= MT1-6 MMPs) Others: (MatrilysinsMMP-7, 26 MetalloelastaseMMP-12

4 NMDA R glutamate proMMP Activation (e.g., by Plasmin) ECM Molecules Ca 2+ Active MMP pre post

5 NMDA R Active MMP ECM Molecules pre post Tissue inhibitors of MMPs (TIMPs)

6 MMP inhibition with FN-439 impairs water maze performance Meighan et al. J. Neurochem. (In Press)

7 Does MMP inhibition prevent acquisition or consolidation of cocaine-induced CPP?

8 + + * + MMP inhibition attenuates acquisition & consolidation of CPP scscscscIPRE3E2E1E4E6E5T aCSF or FN-439 * FN-439 aCSF Test Ext d1 Ext d2Ext d3Ext d4Ext d5 Ext d6 Init Pref C10 Reinstate * * * * * Time spent on cocaine- paired side (sec)

9 C10 Reinstate * * + scscscscIPRE3E2E1E4E6E5T aCSF or FN Test Ext d1Ext d2Ext d3Ext d4Ext d5 Ext d6 * * * * + Init Pref * FN-439 aCSF Time spent on cocaine- paired side (sec) FN-439 aCSF Photocell counts per min spent on cocaine-paired side Activity

10 Does MMP inhibition prevent reconsolidation?

11 scscscscIPRE3E2E1E4E6E5T RR aCSF or FN-439 C10 Reinstate 1 C10 Reinstate 2 C10 Reinstate 3 * * * * * * * C10 Reinstate 1 C10 Reinstate Init. Pref. Test Last ext day FN-439 aCSF MMP Inhibitor in Home Cage Home Cage * * Infusion in MMP inhibition disrupts reconsolidation of CPP Time spent on cocaine- paired side (sec) MMP Inhibitor in CPP Box Init. Pref. Test Last ext day FN-439 aCSF * *

12 scscscscIPRE3E2E1E4E6E5T RR aCSF or FN-439 MMP inhibition disrupts reconsolidation of CPP C10 Reinstate 1 C10 Reinstate 2 C10 Reinstate 3 * * * * * Time spent on cocaine- paired side (sec) MMP Inhibitor in CPP Box Init. Pref. Test Last ext day FN-439 aCSF * * FN-439 aCSF Photocell counts per min spent on cocaine-paired side Activity

13 scscscscIPRE3E2E1E4E6E5T RR aCSF or FN-439 C10 Reinstate 1 C10 Reinstate 2 C10 Reinstate 3 * * * * * * Init Pref Test Ext d1 Ext d2 Ext d3 Ext d4 Ext d5Ext d6 Ext d7 FN-439 aCSF * * * * Time spent on cocaine- paired side (sec) Repeated exposure to MMP inhibitor in context only does not alter reinstatement of CPP

14 Both the context AND cocaine are required to disrupt reconsolidation of the cocaine memory by the MMP inhibitor. Conclusion

15 MMP-3 GAPDH Cocaine Prime Saline Prime Time After Cocaine-Primed Reinstatement MMP-3 mRNA (% Saline) Amygdala hr 3 hr Cocaine Saline * 3 hr Cocaine-Primed Reinstatement Increases MMP-3 mRNA in Amygdala

16 Summary of reconsolidation studies as applied to drug abuse 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 47:795. Disrupt the conditioned reward value of the CS (light) (Pavlovian to instrumental transfer, in absence of drug) Lee et al. (2005) Neuron 47:795. Disrupt the drug-associated contextual memory Disrupt the drug-associated contextual memory (in absence of drug) also, Miller and Marshall (2005) Neuron 47:873. Disrupt the drug-associated contextual memory Disrupt the drug-associated contextual memory (in presence of drug)

17 Motivational output that mediates expression of drug-seeking behavior Drug of Abuse Discrete Drug Cues Contextual Cues Integration of Memory (Nacc?) New contexts and cues? Disrupt Reconsolidation

18 Questions/Challenges Ahead Does disruption of reconsolidation reduce craving (in addition to expression of cocaine-seeking behavior)? If the memory is partially present after disruption of reconsolidation, does relapse to drug-taking cause reconsolidation and therefore strengthening of the memory? Is the memory impairment from disruption of reconsolidation long-lasting, or will “maintenance treatments” be required? Does extinction alter (facilitate or impair) reconsolidation of a drug memory?

19 ? Collaborators: Drs. Joseph Harding & Jay Wright

20 “Use almost can change the stamp of nature” Hamlet Can disruption of reconsolidation change the stamp of drugs?

21

22 Examples of stimuli affecting brain MMPs MMP-2HippocampusSeizures, transient ischemia traumatic brain injury MMP-3Cortextransient ischemia, traumatic brain injury MMP-9HippocampusSpatial learning, Sleep deprivation, Alzheimer’s disease MMP-9CortexSpatial learning, transient ischemia MMP Brain structure Up/downregulation


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