This application will determine the mechanisms underlying a profound dephosphorylation of ERK MAP kinase and in the dorsomedial prefrontal cortex (PFC) during early withdrawal from cocaine self-administration (SA) that trigger persistent cocaine-seeking. We have demonstrated that ERK dephosphorylation (or shutoff) in the PFC occurs within 2 hr of the end of repeated, daily cocaine SA. Reversing the ERK shutoff with a single infusion of brain-derived neurotrophic factor (BDNF) into the PFC normalizes glutamate transmission in the nucleus accumbens and suppresses cocaine-seeking in abstinent animals for as long as three weeks. However, BDNF is not a therapeutically useful medication because it is a neuropeptide that does not effectively cross the blood-brain barrier. Therefore, it is necessary to characterize the molecular mechanisms underlying the cocaine SA-induced ERK shutoff in order to identify alternative targets for medication development. We present a rationale and preliminary evidence to support the hypothesize that the ERK shutoff is mediated by GluN2B receptor activation of the ERK phosphatase, STEP. We propose to investigate this hypothesis in the following aims.
In Aim 1, we will investigate changes in ERK phosphatase activation and the surface expression and synaptic/extrasynaptic distribution of NMDA receptors during early withdrawal from cocaine SA.
In Aim 2, we will investigate whether antagonists of GluN2A or GluN2B receptors will suppress the cocaine-induced ERK/CREB shut-off in the PFC during early withdrawal and persistent cocaine-seeking after abstinence and extinction training.
In Aim 3, we will investigate whether or not inhibition of calcineurin and the ERK phosphatases, STEP or protein phosphatase 2A, will reverse the cocaine-induced ERK/CREB shut-off during early withdrawal and suppress cocaine-seeking after abstinence and extinction training. These studies will impact the field of drug abuse research by advancing our understanding of the key neurobiological substrates that mediate cocaine-induced neuroadaptations and relapse to drug-seeking with the potential of leading to novel preventive interventions during early withdrawal.

Public Health Relevance

Despite the critical nature of cocaine addiction, current preclinical models devoted to investigating the enduring neural substrates of cocaine addiction have yielded little progress in developing new therapeutics. In contrast, this application focuses on intervention during early withdrawal from cocaine self-administration to suppress persistent cocaine-seeking and underlying neuroadaptations. These studies will impact the field of drug abuse research by advancing our understanding of the key neurobiological substrates that mediate early withdrawal- induced neuroadaptations and relapse to drug-seeking with the potential of leading to possible novel therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA033479-03
Application #
8787464
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Pilotte, Nancy S
Project Start
2013-01-01
Project End
2017-12-31
Budget Start
2015-01-01
Budget End
2015-12-31
Support Year
3
Fiscal Year
2015
Total Cost
$281,362
Indirect Cost
$90,112
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29403
Siemsen, Ben M; Lombroso, Paul J; McGinty, Jacqueline F (2018) Intra-prelimbic cortical inhibition of striatal-enriched tyrosine phosphatase suppresses cocaine seeking in rats. Addict Biol 23:219-229
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
Cox, Brittney M; Bentzley, Brandon S; Regen-Tuero, Helaina et al. (2017) Oxytocin Acts in Nucleus Accumbens to Attenuate Methamphetamine Seeking and Demand. Biol Psychiatry 81:949-958
Go, Bok Soon; Barry, Sarah M; McGinty, Jacqueline F (2016) Glutamatergic neurotransmission in the prefrontal cortex mediates the suppressive effect of intra-prelimbic cortical infusion of BDNF on cocaine-seeking. Eur Neuropsychopharmacol 26:1989-1999
McGinty, Jacqueline F; Zelek-Molik, Agnieska; Sun, Wei-Lun (2015) Cocaine self-administration causes signaling deficits in corticostriatal circuitry that are reversed by BDNF in early withdrawal. Brain Res 1628:82-7
Zhou, Luyi; Sun, Wei-Lun; Young, Amy B et al. (2014) Oxytocin reduces cocaine seeking and reverses chronic cocaine-induced changes in glutamate receptor function. Int J Neuropsychopharmacol 18:
Sun, Wei-Lun; Coleman, Nortorious T; Zelek-Molik, Agnieszka et al. (2014) Relapse to cocaine-seeking after abstinence is regulated by cAMP-dependent protein kinase A in the prefrontal cortex. Addict Biol 19:77-86
Sun, Wei-Lun; Zelek-Molik, Agnieszka; McGinty, Jacqueline F (2013) Short and long access to cocaine self-administration activates tyrosine phosphatase STEP and attenuates GluN expression but differentially regulates GluA expression in the prefrontal cortex. Psychopharmacology (Berl) 229:603-13