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.
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.
