Cocaine abuse is a major public health problem in the United States. In the latest national study, the number of people over the age of 12 who are current cocaine users is estimated at 1.6 million, or 0.7% of the total population. In recent years, extensive research has demonstrated that cocaine addiction is associated with neuroadaptations and consequent pathology of reward learning. Chronic cocaine exposure leads to alterations in glutamatergic synapses, including changes in glutamate release, gene and protein expression, and synaptic plasticity. Further elucidating the mechanisms underlying these changes and how they lead lo relapse is the goal of this grant application. More specifically, work utilizing both in vitro slice physiology and in vivo field recordings indicate that repeated exposure to cocaine leads to a decrease in long-term depression within the nucleus accumbens (NAc). Although the exact mechanisms underlying this effect are unclear, existing evidence from the learning and memory field indicates that PKC-mediated AMPA receptor endocytosis is necessary for long-term depression. Additional evidence obtained during the K99 phase of funding indicates that blocking long-term depression, either via potentiating endocytosis via deletion of the anchoring protein glutamate receptor interacting protein (GRIP), or disrupting endocytosis, utilizing a transgenic mouse lacking the PKC phosphorylation site on the AMPA receptor GluA2 subunit, leads to increased reinstatement of drug seeking behavior. Aims proposed for the ROO phase of the grant will expand upon these findings to examine the role AMPA receptor trafficking in stress-induced reinstatement. This will be acomplished using the two lines of mice described above and examining how manipulating AMPA endocytosis alters stress-induced behaviors as well as physiology. None of the aims of the grant have changed since the original K99 submission, however one aim from the K99 phase has been switched with an already-completed aim from the ROO phase, as discussed in the Research Strategy section.