This application focuses on intervention during early withdrawal from cocaine self-administration to suppress persistent cocaine-seeking and underlying neuroadaptations. We have based this approach on findings in which brain-derived neurotrophic factor (BDNF) infused into the dorsomedial prefrontal cortex (dmPFC) of rats immediately after the last cocaine self-administration session suppresses cocaine-seeking in an ERK MAP kinase-dependent manner. BDNF reverses cocaine-induced dephosphorylation of ERK and CREB in the dmPFC within 2 hr after the end of cocaine self-administration. If BDNF administration is delayed after the end of self-administration, it has no effect on cue-induced cocaine-seeking. Thus, the first few hr after the end of repeated cocaine exposure appear to be critical for BDNF's actions. We hypothesize that this timing is linked to the transient nature of ERK and CREB dephosphorylation (or """"""""shutoff') that recovers by 22 hr after the end of cocaine self-administration. Further, preliminary data presented in this proposal implicate the striatal-enriched tyrosine phosphatase (STEP) in cocaine SA-induced ERK dephosphorylation in the dmPFC. Based on this foundation, we will investigate the role of synaptic activity (Aim 1 and 2) and kinase- phosphatase balance (Aims 3 and 4) in the ability of intra-PFC BDNF to normalize ERK phosphorylation in dmPFC during early withdrawal and suppress cocaine-seeking in rats with a cocaine SA history.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
2P50DA015369-11
Application #
8585272
Study Section
Special Emphasis Panel (ZDA1-EXL-T (01))
Project Start
Project End
Budget Start
2013-05-15
Budget End
2014-04-30
Support Year
11
Fiscal Year
2013
Total Cost
$147,881
Indirect Cost
$63,173
Name
Medical University of South Carolina
Department
Type
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
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Spencer, Sade; Kalivas, Peter W (2017) Glutamate Transport: A New Bench to Bedside Mechanism for Treating Drug Abuse. Int J Neuropsychopharmacol 20:797-812
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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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