Drug addiction is a major health issue worldwide, and the central focus of the NIDA Center at RockefellerUniversity. All addictive substances enhance dopamine in the mesolimbic reward circuit from the ventraltegmental area (VTA) to the nucleus accumbens shell (Acb-SH), a limbic brain region included with thecentral nucleus of the amygdala (CeA) and the bed nucleus of the stria terminalis (BNST) as components ofthe extended amygdala. These regions are also targeted by many excitatory inputs, whose physiologicalactions are largely ascribed to activation of glutamate (NMDA and AMP A) receptors. Glutamatergictransmission is potently modulated by dopamine acting at Dl receptors and corticotrophin releasing factor(CRF) peptides active at CRF type-1 (CRF1) receptors that are prevalent in both the central extended andbasolateral (BLA) amygdala. The more cortical-like BLA has bidirectional connections with the VTA-andother limbic structures implicated in emotional behavior and learning of drug/reward associations. Glutamatereceptor plasticity and associations with the dopamine and/or CRF systems contribute to persistent drugseekingbehaviors that are powerfully influenced by stress. The subcellular changes in receptor distributionsoccurring in neurons with these identified transmitter phenotypes in individual brain regions are largelyunknown. To begin addressing these key questions, Project 3 in the renewal application will combineresearch strategies using electron microscopic immunolabeling and spatial-temporal deletion (knock-out) ofthe NR1 NMDA receptor subunit in limbic brain regions critical for drug seeking behaviors. The long-rangegoal is to test the hypotheses that (1) limbic NMDA receptors have subcellular distributions conducive toregionally selective associations with dopamine and CRF systems, and (2) NR1 gene expression in the VTAand/or BLA is essential for the synaptic targeting and cocaine-induced trafficking of both AMP A anddopamine Dl receptors, and for cocaine conditioned place preference (CPP) influenced by stress. The studieswill be conducted in wild-type and NR1 'floxed' (flanked by loxP) mice, some of which will receive acute orchronic (14 day) cocaine given in an escalating 'binge' pattern mimicking that seen in human addicts.Project 3 reflects a collaborative effort by investigators in existing projects within the NIDA Center and istotally dependent on the core resources and facilities. The results obtained from Project 3, together with thosein other projects in the renewal application, will provide important new information that is essential forunderstanding and treating drug addiction.
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