The long-term objectives of Project 2 are to identify novel neurobiological substrates of addiction that will lead to therapeutic advancements in concert with the other NARC projects. Three major findings have emerged from Project 2 in the current budget period. First, an infusion of brain-derived neurotrophic factor (BDNF) into the dorsomedial prefrontal cortex (dmPFC) immediately after the last cocaine self-administration session suppresses extinction responding, cue-, and cocaine-induced reinstatement of cocaine seeking. Although the precise mechanism is unknown, preliminary data suggest that exogenous BDNF is anterogradely transported to the nucleus accumbens (NAc) where it normalizes cocaine-induced alterations in extracellular glutamate and phospho-ERK expression. Second, the expression of a subset of mRNAs that are enriched in dendritic polysomes is altered in the mPFC 22 hr or 3 weeks after the end of cocaine selfadministration. Some of these mRNAs, including BDNF, the protein phosphatase 1 binding protein, spinophilin, protein phosphatase 1 catalytic subunit beta, and the double-stranded RNA-binding protein Staufen 2, are required for the development and maintenance of dendritic spine morphology that may be disturbed in cocaine withdrawal. The molecular mechanisms for these neuroadaptations are thought to include alterations in protein turnover at the postsynaptic density (PSD) in dendritic spines that make excitatory synaptic contacts. Third, relapse to cocaine seeking elicited by re-exposure to the selfadministration chamber increases activity-related genes, including BDNF, in the cerebral cortex and/or striatum of abstinent rats. Thus, our hypothesis is that infusion of BDNF into the dmPFC will prevent cocaine abstinence-induced neuroadaptations in dendritic mRNAs, spine morphology, and relapse-induced alterations in activity genes in the PFC and striatum. This hypothesis will be tested by determining (1) the site and mechanism of action of intra-PFC BDNF's suppressive effects on cocaine seeking, and whether infusion of BDNF into the dmPFC (2) alters cocaine-induced changes in gene and phosphoprotein expression during early abstinence, (3) prevents alterations in the expression of dendritic mRNAs, PSD proteins, and dysmorphic dendritic spines in cocaine-abstinent rats, and (3) prevents alterations in cortical activity markers after contextual relapse. Another important goal is to integrate Project 2 with the other projects of the NARC by using overlapping animal models, providing unique information on the same areas of relapse circuitry, and utilizing the expertise of the other Project leaders to advance our understanding of the neurobiology of addiction as a whole.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
5P50DA015369-10
Application #
8377632
Study Section
Special Emphasis Panel (ZDA1-RXL-E)
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
10
Fiscal Year
2012
Total Cost
$187,865
Indirect Cost
$62,627
Name
Medical University of South Carolina
Department
Type
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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Bobadilla, Ana-Clara; Garcia-Keller, Constanza; Heinsbroek, Jasper A et al. (2017) Accumbens Mechanisms for Cued Sucrose Seeking. Neuropsychopharmacology 42:2377-2386
Smith, Alexander C W; Scofield, Michael D; Heinsbroek, Jasper A et al. (2017) Accumbens nNOS Interneurons Regulate Cocaine Relapse. J Neurosci 37:742-756
Spencer, Sade; Kalivas, Peter W (2017) Glutamate Transport: A New Bench to Bedside Mechanism for Treating Drug Abuse. Int J Neuropsychopharmacol 20:797-812
Moorman, David E; James, Morgan H; Kilroy, Elisabeth A et al. (2017) Orexin/hypocretin-1 receptor antagonism reduces ethanol self-administration and reinstatement selectively in highly-motivated rats. Brain Res 1654:34-42
Barry, Sarah M; McGinty, Jacqueline F (2017) Role of Src Family Kinases in BDNF-Mediated Suppression of Cocaine-Seeking and Prevention of Cocaine-Induced ERK, GluN2A, and GluN2B Dephosphorylation in the Prelimbic Cortex. Neuropsychopharmacology 42:1972-1980
Bobadilla, Ana-Clara; Heinsbroek, Jasper A; Gipson, Cassandra D et al. (2017) Corticostriatal plasticity, neuronal ensembles, and regulation of drug-seeking behavior. Prog Brain Res 235:93-112
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
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
Spencer, Sade; Scofield, Michael; Kalivas, Peter W (2016) The good and bad news about glutamate in drug addiction. J Psychopharmacol 30:1095-1098

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