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Reconsolidation, Cocaine and Matrix Metalloproteinases

Reconsolidation, Cocaine and Matrix Metalloproteinases. Barbara A. Sorg Washington State University. Addiction is Learned. Memory Process. Addiction Process. Learning. First Drug Use. Synaptic Remodeling. Consolidation. Repeated Drug Use. Recall/Reactivation. Drug/Drug Cue

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Reconsolidation, Cocaine and Matrix Metalloproteinases

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

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

  3. Enzyme MMP Collagenases MMPs-1, 8, 13, 18 Gelatinases MMPs-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. Ca2+ proMMP proMMP Activation (e.g., by Plasmin) Active MMP post NMDAR glutamate pre ECM Molecules

  5. Tissue inhibitors of MMPs (TIMPs) post NMDAR pre Active MMP ECM Molecules

  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. * 800 aCSF 700 + 600 FN-439 * 500 Time spent on cocaine- paired side (sec) * 400 * * * + * 300 + 200 100 0 Test Ext d1 Ext d2 Ext d3 Ext d4 Ext d5 Ext d6 Init Pref C10 Reinstate aCSF or FN-439 E1 E2 E3 E4 E5 E6 IP c s c s c s c s T R MMP inhibition attenuates acquisition & consolidation of CPP

  9. * Activity 800 + aCSF 700 aCSF * 600 FN-439 FN-439 * 140 500 * Time spent on cocaine- paired side (sec) * + * * 120 400 Photocell counts per min spent on cocaine-paired side + 100 300 80 200 60 100 40 Test 0 20 Ext d1 Ext d2 Ext d3 Ext d4 Ext d5 Ext d6 Init Pref 0 C10 Reinstate aCSF or FN-439 E1 E2 E3 E4 E5 E6 IP c s c s c s c s T R

  10. Does MMP inhibition prevent reconsolidation?

  11. MMP Inhibitor in CPP Box MMP Inhibitor in Home Cage 700 700 aCSF aCSF * 600 * 600 + * FN-439 FN-439 * 500 500 * + * * Time spent on cocaine- paired side (sec) * * * 400 * 400 Infusion in + 300 300 200 Home 200 Cage 100 100 0 0 Test Test Init. Pref. Init. Pref. Last ext day Last ext day C10 Reinstate 3 C10 Reinstate 3 C10 Reinstate 1 C10 Reinstate 2 C10 Reinstate 1 C10 Reinstate 2 E1 E2 E3 E4 E5 E6 aCSF or FN-439 c s c s c s c s IP T R R R MMP inhibition disrupts reconsolidation of CPP

  12. MMP inhibition disrupts reconsolidation of CPP MMP Inhibitor in CPP Box 700 aCSF * * 600 + * FN-439 * 500 + Time spent on cocaine- paired side (sec) * * * 400 + 300 200 100 0 Test Init. Pref. Last ext day C10 Reinstate 3 C10 Reinstate 1 C10 Reinstate 2 E1 E2 E3 E4 E5 E6 aCSF or FN-439 c s c s c s c s IP T R R R Activity aCSF FN-439 100 75 Photocell counts per min spent on cocaine-paired side 50 25 0

  13. + 800 * * * aCSF * * * 600 FN-439 * * Time spent on cocaine- paired side (sec) * * 400 200 0 Test Ext d2 Ext d3 Ext d5 Ext d6 Ext d1 Ext d4 Ext d7 Init Pref C10 Reinstate 2 C10 Reinstate 1 C10 Reinstate 3 aCSF or FN-439 E1 E2 E3 E4 E5 E6 c s c s c s c s IP T R R R Repeated exposure to MMP inhibitor in context only does not alter reinstatement of CPP

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

  15. Saline Cocaine 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

  16. 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 47:795. • Disrupt the drug-associated contextual memory • (in absence of drug) • also, Miller and Marshall (2005) Neuron 47:873. • Disrupt the drug-associated contextual memory • (in presence of drug)

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

  18. 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?

  19. Evan Sleipness Beezer Cocking Melissa Forquer Travis Brown ? 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. Examples of stimuli affecting brain MMPs MMP Brain structure Up/downregulation MMP-2 Hippocampus Seizures, transient ischemia traumatic brain injury MMP-3 Cortex transient ischemia, traumatic brain injury MMP-9 Hippocampus Spatial learning, Sleep deprivation, Alzheimer’s disease MMP-9 Cortex Spatial learning, transient ischemia

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