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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Neurobiology of Motivated Behavior Study Section (NMB)
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Sorensen, Roger
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Washington State University
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Wright, William J; Dong, Yan (2018) Intrinsic Excitability of Cocaine-Associated Memories. Neuropsychopharmacology 43:675-676
Koya, Eisuke; Dong, Yan (2018) Sound of silent synapses from the addicted hippocampus. Neuropsychopharmacology 43:1981-1982
Cahill, Michael E; Browne, Caleb J; Wang, Junshi et al. (2018) Withdrawal from repeated morphine administration augments expression of the RhoA network in the nucleus accumbens to control synaptic structure. J Neurochem 147:84-98
Wang, Junshi; Ishikawa, Masago; Yang, Yue et al. (2018) Cascades of Homeostatic Dysregulation Promote Incubation of Cocaine Craving. J Neurosci 38:4316-4328
Labonté, Benoit; Engmann, Olivia; Purushothaman, Immanuel et al. (2017) Sex-specific transcriptional signatures in human depression. Nat Med 23:1102-1111
Wright, William J; Schlüter, Oliver M; Dong, Yan (2017) A Feedforward Inhibitory Circuit Mediated by CB1-Expressing Fast-Spiking Interneurons in the Nucleus Accumbens. Neuropsychopharmacology 42:1146-1156
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) 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

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