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.
|Dong, Yan; Nestler, Eric J (2014) The neural rejuvenation hypothesis of cocaine addiction. Trends Pharmacol Sci 35:374-83|
|Ma, Yao-Ying; Lee, Brian R; Wang, Xiusong et al. (2014) Bidirectional modulation of incubation of cocaine craving by silent synapse-based remodeling of prefrontal cortex to accumbens projections. Neuron 83:1453-67|
|Bonnet, Stephanie A D; Akad, Derya S; Samaddar, Tanmoy et al. (2013) Synaptic state-dependent functional interplay between postsynaptic density-95 and synapse-associated protein 102. J Neurosci 33:13398-409|
|Otaka, Mami; Ishikawa, Masago; Lee, Brian R et al. (2013) Exposure to cocaine regulates inhibitory synaptic transmission in the nucleus accumbens. J Neurosci 33:6753-8|
|Lee, Brian R; Ma, Yao-Ying; Huang, Yanhua H et al. (2013) Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving. Nat Neurosci 16:1644-51|
|Ishikawa, Masago; Otaka, Mami; Huang, Yanhua H et al. (2013) Dopamine triggers heterosynaptic plasticity. J Neurosci 33:6759-65|
|Huang, Yanhua H; Schluter, Oliver M; Dong, Yan (2013) An unusual suspect in cocaine addiction. Neuron 80:835-6|
|Ishikawa, Masago; Otaka, Mami; Neumann, Peter A et al. (2013) Exposure to cocaine regulates inhibitory synaptic transmission from the ventral tegmental area to the nucleus accumbens. J Physiol 591:4827-41|
|Chen, Bo; Ma, Yao-Ying; Wang, Yao et al. (2013) Cocaine-induced membrane adaptation in the central nucleus of amygdala. Neuropsychopharmacology 38:2240-8|
|Browning, Jenny R; Browning, Douglas A; Maxwell, Alexis O et al. (2011) Positive affective vocalizations during cocaine and sucrose self-administration: a model for spontaneous drug desire in rats. Neuropharmacology 61:268-75|
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