Our long-term goal is to understand the mechanistic details that underlie the formation of nascent synapses after repeated cocaine exposure. The objective of this application is to use cocaine self- administration, viral-mediated gene transfer and electrophysiological assays to begin to elucidate the formation of these synapses. Within the limbic system, three major glutamatergic afferents that synapse onto NAc neurons originate from the prefrontal cortex (PFC), hippocampus, and the amygdala. Given that these three afferents play distinct roles in addictive behaviors, identifying the specific afferents that undergo cocaine-induced generation of nascent synapses and thus circuitry reorganization will provide a circuitry- based understanding of different aspects of the addictive state. The central hypothesis of the application is that self-administration of cocaine increases the number of silent synapses in NAc neurons among the PFC afferent and that this increase is correlated with an enhancement in the ability to learn about drug reward;thus, forming an apparent pathological memory. We plan to test our hypotheses by pursuing the following two aims: 1) Determine the effect of the contingency of cocaine administration on silent synapses development;and, 2) Establish the glutamatergic afferent to the NAc that express cocaine-generated silent synapses. The proposed work is innovative because it will further our understanding of the cellular and molecular changes that accompany cocaine exposure. Silent synapses have been shown to be crucial in the development of synapses and circuitry in the developing brain. If we can understand the development of addiction from this novel angle, more accurate pharmacological manipulations can be designed for future clinical interventions to block and/or reverse pro-addiction cellular adaptations.

Public Health Relevance

Nerve cells change their connections upon exposure to cocaine, and such cocaine- induced changes are thought to contribute addiction-related behaviors. This application aims to characterize the molecular mechanisms underlying cocaine-induced re- organization of neural circuitry. Outcomes of the proposed work are expected to provide mechanism-based strategies for the treatment of cocaine addiction and this benefits public health.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31DA028020-03
Application #
8293292
Study Section
Special Emphasis Panel (ZRG1-F02A-J (20))
Program Officer
Babecki, Beth
Project Start
2010-07-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$42,232
Indirect Cost
Name
Washington State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
041485301
City
Pullman
State
WA
Country
United States
Zip Code
99164
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
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
Brown, Travis E; Lee, Brian R; Mu, Ping et al. (2011) A silent synapse-based mechanism for cocaine-induced locomotor sensitization. J Neurosci 31:8163-74
Huang, Yanhua H; Ishikawa, Masago; Lee, Brian R et al. (2011) Searching for presynaptic NMDA receptors in the nucleus accumbens. J Neurosci 31:18453-63
Lee, Brian R; Dong, Yan (2011) Cocaine-induced metaplasticity in the nucleus accumbens: silent synapse and beyond. Neuropharmacology 61:1060-9