The ability to attenuate drug-associated memories in drug addicts is important because this attenuation is expected to suppress the cycle of relapse to drugs. Persistent drug-taking behavior involves consolidation of memory for the drug and drug-associated cues and contexts. When a memory is reactivated (retrieved), that memory becomes labile and susceptible to disruption by amnestic agents (e.g., protein synthesis inhibitors) present at the time of reactivation. Drug abuse studies in rodents indicate that reconsolidation can be disrupted, and this is manifest as suppressed drug-seeking behavior when animals are subsequently primed with the same stimulus used to reactivate the memory. Most studies have focused on drug-induced conditioned place preference (CPP); since only a few drug injections are given with CPP, the memories may be relatively easy to disrupt. However, few labs have focused on the rat self-administration model, which has higher face validity for human addiction. To date, no self-administration studies have attempted to disrupt reconsolidation of the memory associated with the drug itself, when the drug is present during reactivation and subsequent reinstatement. This is significant because the drug induces powerful reinstatement in rats and augments relapse in humans. We present for the first time data showing that administration of amnestic agents into the medial prefrontal cortex (mPFC) during reactivation of a cocaine- associated memory suppresses subsequent cocaine-primed reinstatement when amnestic agents are no longer present. The focus of this proposal is on one of these agents, an inhibitor of matrix metalloproteinases (MMPs). MMPs belong to a family of metalloendopeptidases that can direct changes in synaptic morphology via their effects on the extracellular matrix (ECM). Some components of the ECM are densely organized into perineuronal nets (PNNs) that ensheath primarily inhibitory interneurons in the cortex. Based on our work and that of others, we believe that MMPs are involved in maintaining as well as diminishing cocaine-related memories. We hypothesize that components of the ECM within PNNs must be transiently degraded by MMPs during synaptic remodeling to permit the reconsolidation of memory. We will test our hypothesis in three Specific Aims:
Specific Aim 1 will determine the extent to which inhibition of MMPs in the mPFC suppresses MMP activity and increases PNN density and PNN glycoprotein levels.
Specific Aim 2 will determine the extent to which MMP inhibition in the mPFC disrupts reconsolidation of cocaine-associated memories in self-administering rats.
Specific Aim 3 will determine the impact of MMP inhibition on c-Fos activation in PNN-containing interneurons in the mPFC and whether dynamic changes in PNNs are a key mechanistic step for MMP effects on cocaine-associated memories. These studies will have a positive impact on the drug abuse field because they will determine the potential for using MMP inhibitors to disrupt reconsolidation of cocaine memories that may underlie chronic relapse.

Public Health Relevance

The proposed studies will determine the extent to which cocaine-associated memories are able to be disrupted in a rat self-administration model. Disruption of these memories is expected to suppress the motivation to seek or take cocaine. These studies have high translational potential in humans because successful disruption of learned drug-associated memories would help break the cycle of relapse in human cocaine addicts.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA033404-04
Application #
8849419
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Sorensen, Roger
Project Start
2012-06-15
Project End
2016-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
4
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Washington State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164
Su, Weiping; Matsumoto, Steven; Sorg, Barbara et al. (2018) Distinct roles for hyaluronan in neural stem cell niches and perineuronal nets. Matrix Biol :
Slaker, Megan L; Jorgensen, Emily T; Hegarty, Deborah M et al. (2018) Cocaine Exposure Modulates Perineuronal Nets and Synaptic Excitability of Fast-Spiking Interneurons in the Medial Prefrontal Cortex. eNeuro 5:
Blacktop, Jordan M; Sorg, Barbara A (2018) Perineuronal nets in the lateral hypothalamus area regulate cue-induced reinstatement of cocaine-seeking behavior. Neuropsychopharmacology :
Harkness, John H; Bushana, Priyanka N; Todd, Ryan P et al. (2018) Sleep disruption elevates oxidative stress in parvalbumin-positive cells of the rat cerebral cortex. Sleep :
Blacktop, Jordan M; Todd, Ryan P; Sorg, Barbara A (2017) Role of perineuronal nets in the anterior dorsal lateral hypothalamic area in the acquisition of cocaine-induced conditioned place preference and self-administration. Neuropharmacology 118:124-136
Slaker, Megan; Barnes, Jesse; Sorg, Barbara A et al. (2016) Impact of Environmental Enrichment on Perineuronal Nets in the Prefrontal Cortex following Early and Late Abstinence from Sucrose Self-Administration in Rats. PLoS One 11:e0168256
Slaker, Megan; Blacktop, Jordan M; Sorg, Barbara A (2016) Caught in the Net: Perineuronal Nets and Addiction. Neural Plast 2016:7538208
Zhang, Xing; Chiu, Veronica M; Todd, Ryan P et al. (2016) Neuronal metabolomics by ion mobility mass spectrometry in cocaine self-administering rats after early and late withdrawal. Anal Bioanal Chem 408:4233-45
Sorg, Barbara A; Berretta, Sabina; Blacktop, Jordan M et al. (2016) Casting a Wide Net: Role of Perineuronal Nets in Neural Plasticity. J Neurosci 36:11459-11468
Slaker, Megan L; Harkness, John H; Sorg, Barbara A (2016) A standardized and automated method of perineuronal net analysis using Wisteria floribunda agglutinin staining intensity. IBRO Rep 1:54-60

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