My lab has played an important role over the past 20 years in showing that neuronal adaptations leading to drug addiction involve glutamate-dependent plasticity. Our recent work is based on evidence that the final common pathway for drug seeking involves cortical and limbic glutamate inputs terminating on nucleus accumbens (NAc) neurons, which in turn project to motor regions responsible for execution of drug seeking. These glutamate inputs activate NAc neurons via AMPA-type glutamate receptors (AMPAR). In light of the importance of AMPAR trafficking for controlling synaptic strength, we are testing the hypothesis that increased trafficking of AMPAR into NAc synapses underlies the enhancement of cocaine seeking that occurs after withdrawal from cocaine exposure. Since 2000, I have been supported by a NIDA K02 Award. Protected time and salary savings afforded by the K02 enabled my lab to develop the innovative methods that led to our current focus on AMPAR trafficking. As a result, we were the first to study AMPAR trafficking in NAc neurons and to establish its importance in rat models of cocaine addiction (behavioral sensitization and incubation of cue-induced cocaine craving after withdrawal from cocaine self-administration). Advances facilitated by the K02 Award led to a NIDA Merit Award and to the continued funding of my R01. These grants focus on defining fundamental properties of AMPAR transmission in the NAc and understanding the mechanisms by which cocaine exposure influences AMPAR trafficking. Recent work funded by these grants has shown that an atypical AMPAR subtype, added to NAc synapses after prolonged withdrawal, mediates enhanced cocaine craving and is therefore a target for the development of anti-craving medications. I am applying for a K05 Award to maintain relief from teaching and service duties so that I can most effectively pursue the Aims of my NIDA grants and position my lab for even stronger contributions to the field through continued innovation. In particular, there are two New Research Directions that I propose to pursue in order to enhance my career development and accelerate our progress towards understanding plasticity mechanisms that contribute to cocaine addiction. First, I want to develop methods to analyze dendritic spine morphology and number, so that I can test the hypothesis that AMPAR synaptic insertion triggers dendritic remodeling in the NAc after cocaine withdrawal. Second, I want to develop the capability to use viral- mediated gene delivery to more effectively explore signaling pathways that underlie cocaine-induced AMPAR, structural and behavioral plasticity. I have identified two expert consultants to assist with the development of these new directions. In addition, protected time resulting from this K05 Award will enable me to expand my contributions as a mentor. This application contains a detailed plan for mentoring young investigators, particularly three Assistant Professors at my institution who I am helping with overall career development as well as the development of NIDA-funded projects.
Learning plays an important role in addiction. For example, environmental cues that addicts have learned to associate with drug availability are powerful triggers for relapse, even long after abstinence is achieved. Our goal is to understand the role of glutamate neurotransmission in addiction-related learning and plasticity, with the goal of identifying targets for the development of anti-craving medications.
|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|
|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|
|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|
|Loweth, Jessica A; Scheyer, Andrew F; Milovanovic, Mike et al. (2014) Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving. Nat Neurosci 17:73-80|
|Loweth, Jessica A; Tseng, Kuei Y; Wolf, Marina E (2014) Adaptations in AMPA receptor transmission in the nucleus accumbens contributing to incubation of cocaine craving. Neuropharmacology 76 Pt B:287-300|
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