Trafficking of glutamate receptors in and out of synapses is an important mechanism for regulating synaptic strength during several types of activity-dependent plasticity, including LTP, LTD and synaptic scaling. Addiction is believed to involve maladaptive neuronal plasticity that rewires motivational circuits, focusing behaviors on drug-seeking. The goal of this study is to use a newly adapted assay to determine whether receptor trafficking contributes to the neuronal plasticity produced by in vivo cocaine exposure, focusing on the nucleus accumbens (NAc) because of its key role in drug reward. Briefly, NAc brain slices are prepared from drug-treated rats and incubated with BS3, a membrane impermeant protein crosslinking agent. BS3 electively crosslinks cell surface receptors, forming high molecular weight aggregates that can be distinguished from intracellular receptors by SDS-PAGE and Western blotting. Using this method, we will irst investigate mechanisms regulating glutamate receptor surface expression in the NAc of naive rats and then characterize changes in glutamate and dopamine (DA) receptor surface expression associatedwith behavioral sensitization to cocaine and cocaine self-administration. In preliminary studies, we found that cocaine-sensitized rats exhibit an increase in AMPA receptor surface expression in the NAc that is correlated with the magnitude of behavioral sensitization.
Aim 1 will investigate the role of several protein kinases in regulating glutamate receptor surface expression in NAc slices from naive rats: cyclic AMP-dependent protein kinase (PKA), Ca2+/camodulin dependent protein kinase II (CaMKII), and the mitogen-activated protein kinases ERK1/2 and p38 MAPK. They were selected for study because they are important for AMPA receptor trafficking during LTP and also for addiction-related plasticity.
In Aim 2, we will determine if acute DA receptor stimulation modulates glutamate receptor trafficking in NAc slices and in vivo, and study the involvement of PKA and ERK1/2 in this modulation.
Aim 3 will extend our preliminary studies of cocaine- sensitized rats by examining surface expression of other glutamate receptor subunits and DA receptors, and by evaluating potential correlations between receptor redistribution and activation of signaling pathways. Finally, we will test the hypothesis that intensification (""""""""incubation"""""""") of cocaine craving during withdrawal from cocaine self-administration is associated with increased AMPA receptor surface expression in the NAc, enabling more effective activation of NAc neurons by corticolimbic glutamate inputs involved in drug seeking. Relevance to Public Health: Stress or environmental cues associated with cocaine may trigger craving in addicts because their nucleus accumbens neurons are more responsive to the neurotransmitter glutamate. Our study will provide information on how cocaine changes the responsiveness of these neurons. This in turn may help in the design of glutamate-based pharmacological therapies for cocaine craving.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA009621-14
Application #
7795232
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Frankenheim, Jerry
Project Start
1996-09-01
Project End
2011-03-30
Budget Start
2010-04-01
Budget End
2011-03-30
Support Year
14
Fiscal Year
2010
Total Cost
$282,150
Indirect Cost
Name
Rosalind Franklin University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
069501252
City
North Chicago
State
IL
Country
United States
Zip Code
60064
Werner, Craig T; Murray, Conor H; Reimers, Jeremy M et al. (2017) Trafficking of calcium-permeable and calcium-impermeable AMPA receptors in nucleus accumbens medium spiny neurons co-cultured with prefrontal cortex neurons. Neuropharmacology 116:224-232
Christian, Daniel T; Wang, Xiaoting; Chen, Eugenia L et al. (2017) Dynamic Alterations of Rat Nucleus Accumbens Dendritic Spines over 2 Months of Abstinence from Extended-Access Cocaine Self-Administration. Neuropsychopharmacology 42:748-756
Dong, Yan; Taylor, Jane R; Wolf, Marina E et al. (2017) Circuit and Synaptic Plasticity Mechanisms of Drug Relapse. J Neurosci 37:10867-10876
Scheyer, Andrew F; Loweth, Jessica A; Christian, Daniel T et al. (2016) AMPA Receptor Plasticity in Accumbens Core Contributes to Incubation of Methamphetamine Craving. Biol Psychiatry 80:661-670
Wolf, Marina E (2016) Synaptic mechanisms underlying persistent cocaine craving. Nat Rev Neurosci 17:351-65
Purgianto, Anthony; Loweth, Jessica A; Miao, Julia J et al. (2016) Surface expression of GABAA receptors in the rat nucleus accumbens is increased in early but not late withdrawal from extended-access cocaine self-administration. Brain Res 1642:336-343
Li, Xuan; Wolf, Marina E (2015) Multiple faces of BDNF in cocaine addiction. Behav Brain Res 279:240-54
Werner, Craig T; Milovanovic, Mike; Christian, Daniel T et al. (2015) Response of the Ubiquitin-Proteasome System to Memory Retrieval After Extended-Access Cocaine or Saline Self-Administration. Neuropsychopharmacology 40:3006-14
Selvakumar, Balakrishnan; Campbell, Peter W; Milovanovic, Mike et al. (2014) AMPA receptor upregulation in the nucleus accumbens shell of cocaine-sensitized rats depends upon S-nitrosylation of stargazin. Neuropharmacology 77:28-38
Scheyer, Andrew F; Wolf, Marina E; Tseng, Kuei Y (2014) A protein synthesis-dependent mechanism sustains calcium-permeable AMPA receptor transmission in nucleus accumbens synapses during withdrawal from cocaine self-administration. J Neurosci 34:3095-100

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