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.
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|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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