The leading hypothesis in addiction research is that exposure to drugs of abuse induces adaptive neu- ronal changes, resulting in addictive behaviors. The many experiments conducted on the basis of this neuro-adaptation theory have identified a huge number of drug-induced cellular changes related to addic- tion. For clinical treatment, however, it is impossible to directly manipulate each of these changes. Our long-term research goal is, thus, to identify the molecular `controllers'that trigger and maintain drug-induced neural adaptations;manipulations of these key molecules may then collectively correct other subordinate pathophysiological cellular changes. This proposal focuses on the N-methyl-D-aspartate receptor (NMDAR), a key molecule that governs multiple forms of neural plasticity and that is a potential molecular controller of addiction-related neural adaptations. Our preliminary studies show that cocaine exposure persistently alters the function of NMDARs in nucleus accumbens (NAc) neurons;experimentally mimicking this change of NMDARs triggers secondary cellular adaptations related to addiction. We hypothesize that this cocaine- induced NMDAR adaptation steers a collection of NMDAR-dependent cellular processes toward addiction- specific adaptations. In this application, we propose an extensive but realistic set of experiments to (1) further characterize cocaine-induced adaptation in NAc NMDARs, (2) examine the underlying molecular mechanisms, and (3) investigate the cellular consequences. To achieve these goals we will use a multi- disciplinary approach utilizing patch-clamp recordings, viral-mediated gene transfer, biochemical assays, and behavioral tests. Relevance to Public Health: By characterizing this novel NMDAR adaptation, our proposed study will define a potential molecular trigger for persistent cocaine-induced adaptations, thus providing relevant mechanistic insights to underpin advances in prevention and treatment of addiction.

Public Health Relevance

Project Narrative: The proposed studies will characterize a key molecule that potentially controls a large collection of cocaine-induced, addiction-related neural adaptations. Results from our proposed research will have significant impact on public health because once this `controlling molecule'is defined, therapeutic strategies can be designed accordingly to correct a great number of cocaine-induced cellular adaptations. As such, the findings are expected to lead to novel and effective treatments for human addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
7R01DA023206-06
Application #
8535978
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Sorensen, Roger
Project Start
2008-03-01
Project End
2013-02-28
Budget Start
2012-07-01
Budget End
2013-02-28
Support Year
6
Fiscal Year
2012
Total Cost
$107,827
Indirect Cost
$36,949
Name
University of Pittsburgh
Department
Neurosciences
Type
Schools of Arts and Sciences
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Shukla, Avani; Beroun, Anna; Panopoulou, Myrto et al. (2017) Calcium-permeable AMPA receptors and silent synapses in cocaine-conditioned place preference. EMBO J 36:458-474
Wright, William J; Schl├╝ter, Oliver M; Dong, Yan (2017) A Feedforward Inhibitory Circuit Mediated by CB1-Expressing Fast-Spiking Interneurons in the Nucleus Accumbens. Neuropsychopharmacology 42:1146-1156
Wright, William J; Dong, Yan (2017) Tipping the Scales Toward Addiction. Biol Psychiatry 81:903-904
Liu, Yanling; Cui, Lei; Schwarz, Martin K et al. (2017) Adrenergic Gate Release for Spike Timing-Dependent Synaptic Potentiation. Neuron 93:394-408
Yu, Jun; Yan, Yijin; Li, King-Lun et al. (2017) Nucleus accumbens feedforward inhibition circuit promotes cocaine self-administration. Proc Natl Acad Sci U S A 114:E8750-E8759
Dong, Yan; Taylor, Jane R; Wolf, Marina E et al. (2017) Circuit and Synaptic Plasticity Mechanisms of Drug Relapse. J Neurosci 37:10867-10876
Wright, William J; Dong, Yan (2017) Intrinsic Excitability of Cocaine-Associated Memories. Neuropsychopharmacology :
Dong, Yan (2016) Silent Synapse-Based Circuitry Remodeling in Drug Addiction. Int J Neuropsychopharmacol 19:
Graziane, Nicholas M; Sun, Shichao; Wright, William J et al. (2016) Opposing mechanisms mediate morphine- and cocaine-induced generation of silent synapses. Nat Neurosci 19:915-25
Liu, Zheng; Wang, Yao; Cai, Li et al. (2016) Prefrontal Cortex to Accumbens Projections in Sleep Regulation of Reward. J Neurosci 36:7897-910

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