Drug addiction is a behavioral pathology associated with impairments at excitatory synapses in the nucleus accumbens. The continuing premise of this proposal is that it is possible to pharmacologically repair this impairment(s) and thereby ameliorate the vulnerability to relapse. The possibility that enduring drug-induced changes in accumbens excitatory synapses can be biomarkers for drug addiction has attracted substantial experimental attention over the last 15 years. However, although the behavioral criteria defining drug dependence are shared, including an enduring vulnerability to relapse, many enduring neuroadaptations are not recapitulated between different chemical classes addictive drug. We have explored an approach that drug- induced cellular neuroadaptations shared in common between distinct classes of addictive drug, but not sucrose, may be strong candidate pathologies underpinning the shared behavioral symptoms of addiction. During the previous funding period we and others demonstrated that a shared characteristic between cocaine, heroin, nicotine and alcohol, but not sucrose, is the down-regulation of glial glutamate transport in the core of the nucleus accumbens (NAcore). We also recently discovered that the resulting spillover of synaptic glutamate during reinstated drug seeking initiates transient long-term potentiation (t-LTP) at glutamatergic synapses in NAcore, and this process is regulated by activating matrix metalloprotease-9 (MMP-9) in heroin, cocaine- and nicotine-, but not sucrose-trained rats. MMP-9 is an inducible metalloproteinase that degrades the extracellular matrix (ECM) and thereby signals synaptic plasticity at glutamatergic synapses, such as changes in spine morphology and amplitude of AMPA- mediated currents. The primary experimental goals in continuing this project are to identify the signaling and pathophysiological mechanisms in NAcore that link synaptic glutamate spillover and activating MMP-9 to the subsequent t-LTP that is necessary for reinstating drug seeking. To support the possibility that this sequence of cellula events is a mediator of relapse, we will determine if the signaling mechanisms are shared by animals trained to self-administer heroin and cocaine, but not sucrose.

Public Health Relevance

Drug addiction is a major neuropsychiatric disease in the USA. The proposed research continues our study into the changes in brain cells that cause relapse to using addictive drugs. We will determine which cell groups and the molecular sequence of events that are altered by addictive drugs, and in doing so, we endeavor to identify new targets for small molecule interventions to treat drug addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA003906-34
Application #
9265058
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Berton, Olivier Roland
Project Start
1984-12-01
Project End
2020-04-30
Budget Start
2017-05-01
Budget End
2018-04-30
Support Year
34
Fiscal Year
2017
Total Cost
$314,726
Indirect Cost
$103,226
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29403
Roberts-Wolfe, Douglas; Bobadilla, Ana-Clara; Heinsbroek, Jasper A et al. (2018) Drug Refraining and Seeking Potentiate Synapses on Distinct Populations of Accumbens Medium Spiny Neurons. J Neurosci 38:7100-7107
Spencer, Sade; Neuhofer, Daniela; Chioma, Vivian C et al. (2018) A Model of ?9-Tetrahydrocannabinol Self-administration and Reinstatement That Alters Synaptic Plasticity in Nucleus Accumbens. Biol Psychiatry 84:601-610
Neuhofer, Daniela; Kalivas, Peter (2018) Metaplasticity at the addicted tetrapartite synapse: A common denominator of drug induced adaptations and potential treatment target for addiction. Neurobiol Learn Mem 154:97-111
Kupchik, Yonatan M; Kalivas, Peter W (2017) The Direct and Indirect Pathways of the Nucleus Accumbens are not What You Think. Neuropsychopharmacology 42:369-370
Smith, Alexander C W; Scofield, Michael D; Heinsbroek, Jasper A et al. (2017) Accumbens nNOS Interneurons Regulate Cocaine Relapse. J Neurosci 37:742-756
Taniguchi, Makoto; Carreira, Maria B; Cooper, Yonatan A et al. (2017) HDAC5 and Its Target Gene, Npas4, Function in the Nucleus Accumbens to Regulate Cocaine-Conditioned Behaviors. Neuron 96:130-144.e6
Brown, Robyn Mary; Kupchik, Yonatan Michael; Spencer, Sade et al. (2017) Addiction-like Synaptic Impairments in Diet-Induced Obesity. Biol Psychiatry 81:797-806
Bobadilla, Ana-Clara; Garcia-Keller, Constanza; Heinsbroek, Jasper A et al. (2017) Accumbens Mechanisms for Cued Sucrose Seeking. Neuropsychopharmacology 42:2377-2386
Spencer, Sade; Garcia-Keller, Constanza; Roberts-Wolfe, Douglas et al. (2017) Cocaine Use Reverses Striatal Plasticity Produced During Cocaine Seeking. Biol Psychiatry 81:616-624
Heinsbroek, Jasper A; Neuhofer, Daniela N; Griffin 3rd, William C et al. (2017) Loss of Plasticity in the D2-Accumbens Pallidal Pathway Promotes Cocaine Seeking. J Neurosci 37:757-767

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