COCAINE-INDUCED CIRCUITRY REORGANIZATION WITHIN THE NUCLEUS ACCUMBENS

Brian Robert Lee

Drug addiction has been conceptualized as an extreme form of memory, often viewed as a pathological memory. The molecular and cellular mechanisms responsible for this pathological state are just beginning to be examined. The nucleus accumbens (NAc) plays a pivotal role in the development of addictive behaviors and receives extensive glutamatergic projections from cortical and limbic regions. Glutamate is a key excitatory neurotransmitter responsible for synaptic communication in the nervous system. Cocaine exposure appears to alter these projection neurons to form new nonfunctional synaptic connections known as nascent or silent synapses onto NAc medium spiny neurons (MSNs). Silent synapses are a type of glutamatergic synapse that contains N-methyl-D-aspartic acid receptors (NMDARs) but lacks stable alpha-amino-2-hydroxy-5-methyl-4-isoxazoleprionic acid receptors (AMPARs), which are either absent or highly labile. Upon repeated exposure to cocaine, new NMDARs containing the NR2B subunit are inserted into the postsynaptic membrane. We hypothesized that these NR2B-containing NMDARs play a role in cocaine-elicited locomotor sensitization. Blockade of NR2B-containing NMDARs by chronic administration of Ro256981 directly into the NAc prevented the development of cocaine-elicited locomotor sensitization. Using viral-mediated genetic manipulations we showed that dominant-negative cAMP-element binding protein (CREB) prevents cocaine-induced generation of silent synapses, whereas constitutively active CREB mimics cocaine by generating silent synapses and increasing the number of NR2B-containing NMDARs. Silent synapses generated de novo in NAc MSNs have the potential to arise from multiple afferents. To investigate these possible sources, we used an optogenetic approach to electrophysiologically dissect individual afferents. Due to their prominent role in addiction-related behaviors, we chose to examine the PFC and amygdala afferents and their roles in presynaptic release and in the generation and maturation of silent synapses. We show that these two excitatory afferents are differentially re-organized after passive and active cocaine administrations of cocaine. Specifically, passive cocaine exposure selectively generates silent synapses within PFC afferents, whereas active exposure generates silent synapses within both PFC and amygdala afferents. During long-term withdrawal, newly-generated silent synapses become un-silenced by the recruitment of GluR2-lacking AMPARs, thus qualitatively reshaping excitatory synaptic transmission within these two afferents. These results taken together demonstrate a circuitry re-organization that may mediate cocaine-induced long-term behavioral alterations.

COCAINE-INDUCED CIRCUITRY REORGANIZATION WITHIN THE NUCLEUS ACCUMBENS

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