Project Summary Impairments in cognitive function are among the “hallmark” characteristics of addiction. In this regard, alcoholism is associated with dysfunction of multiple cognitive faculties that may underlie the difficulties in reversing alcohol- seeking behaviors during extended periods of abstinence. Repeated cycles of alcohol intoxication and withdrawal dysregulate brain amino acid systems, an effect that is thought to impart a hyperexcitable state. Whereas acute withdrawal mobilizes signaling of the primary excitatory neurotransmitter glutamate, over time these neurological disturbances subside. The emergence of cognitive disruptions during protracted withdrawal suggests an underlying dysfunction in the medial prefrontal cortex (mPFC). In this regard, drugs of abuse mobilize protein kinases that, over the course of repeated exposures, produce long-term changes in synaptic function and molecular signaling networks that coincide with addictive phenotypes. We propose that withdrawal- induced cognitive impairments relate to an undercurrent of dysfunctional kinase signaling pathways that preserve aberrant glutamate receptor signaling in discrete regions of the mPFC. To this end, the K99 phase will involve training in novel proteomic enrichment strategies to broadly evaluate the mPFC proteome, as isolated by dorsal and ventral regions, towards the goal of identifying novel protein signaling targets in alcohol-dependent rats experiencing protracted withdrawal. We will then seek to characterize the molecular and cognitive behavioral relevance of these targets throughout the R00 phase using novel peptidomimetic strategies that target the disruption of specific protein-protein interactions. This study will provide novel insight into distinct signaling pathways that underlie alcohol-induced cognitive dysfunction.