This is a request for extension of Merit Award DA015835. This Award focused on a fundamental question: how do psychomotorstimulants modulate synaptic plasticity at excitatory synapses? To address this, we conducted the first studies of AMPA receptor trafficking, a critical mechanism for regulating synaptic strength, in primary cultures from the nucleus accumbens (NAc) and other reward-related brain regions. We showed that D1 receptors facilitate AMPA receptor synaptic incorporation, providing a mechanism to explain D1 receptor-dependent facilitation of LTP and learning in the normal brain. Abnormal engagement of this mechanism during unregulated DA release may account for maladaptive plasticity during repeated exposure to cocaine. In the next funding period, we will continue to address fundamental questions about plasticity in reward-related brain regions. In particular, we want to understand mechanisms underlying our recent observation that cell surface AMPA receptor levels in the NAc are increased in 2 animal models of addiction: behavioral sensitization and incubation of cocaine craving.
Aim 1 will determine the subunit composition of AMPA receptor populations in NAc and other addiction-related brain regions. It is critical to know subunit composition, as this determines many features of plasticity.
Aim 2 will focus on TARPs (transmembrane AMPA receptor regulatory proteins), a recently discovered family of proteins that regulates AMPA receptor trafficking and function. We will examine TARP localization and function in NAc neurons, the role of TARP phosphorylation in AMPA receptor trafficking, and the role of TARPs in AMPA receptor adaptations that occur in behavioral sensitization and incubation.
Aim 3 will focus on synaptic scaling, an important form of homeostatic plasticity in which surface and synaptic expression of AMPA receptors upregulates in response to prolonged hypoactivity of excitatory transmission and downregulates in response to prolonged hyper- activity. We will characterize changes in expression and localization of AMPA receptor subunits and TARPs during synaptic scaling in NAc neurons, as well as TARP phosphorylation. We hypothesize that synaptic scaling, triggered by hypoactivity of cortical inputs during cocaine withdrawal, is responsible for AMPA receptor upregulation in the NAc during sensitization and incubation. Public health relevance: Understanding plasticity mechanisms in addiction will help develop therapies aimed at """"""""unlearning"""""""" cues that elicit craving.
|Scheyer, Andrew F; Christian, Daniel T; Wolf, Marina E et al. (2018) Emergence of Endocytosis-Dependent mGlu1 LTD at Nucleus Accumbens Synapses After Withdrawal From Cocaine Self-Administration. Front Synaptic Neurosci 10:36|
|Werner, Craig T; Stefanik, Michael T; Milovanovic, Mike et al. (2018) Protein Translation in the Nucleus Accumbens Is Dysregulated during Cocaine Withdrawal and Required for Expression of Incubation of Cocaine Craving. J Neurosci 38:2683-2697|
|Wang, Junshi; Ishikawa, Masago; Yang, Yue et al. (2018) Cascades of Homeostatic Dysregulation Promote Incubation of Cocaine Craving. J Neurosci 38:4316-4328|
|Dong, Yan; Taylor, Jane R; Wolf, Marina E et al. (2017) Circuit and Synaptic Plasticity Mechanisms of Drug Relapse. J Neurosci 37:10867-10876|
|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|
|Wolf, Marina E (2016) Synaptic mechanisms underlying persistent cocaine craving. Nat Rev Neurosci 17:351-65|
|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|
|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|
Showing the most recent 10 out of 44 publications