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.
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.
|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; 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|
|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|
Showing the most recent 10 out of 45 publications