The current grant proposal seeks to determine the role ofthe 5-HT1A receptor system in the neuroplasticity of cocaine addiction, especially in association with comorbid mood disorders. Although we acknowledge the role ofthe serotonergic system in various CNS functions including addiction, mood disorders and cognition, it is still unclear how and in which direction each 5-HT receptor subtype contributes to these brain dysfunctions. Therefore, with the support of my K99 award, I have begun to investigate how 5-HT1A receptor system is altered during repeated cycles of drug use and withdrawal using a rodent model of drug self-administration with extended access. Research data during the K99 phase suggest that neuadaptations in the 5-HT1A system is related to increased cocaine intake with extended access in rats and that the 5-HT1A system adaptations in cocaine addiction may be associated with that of mood disorders such that one state facilitates the development ofthe other. With the support ofthe ROO award, I will further investigate in which brain regions the neuroadaptations of of 5-HT1A system in cocaine addiction occur and which intracellular signaling pathway underlies the altered 5-HT1A receptor system. In Specific Aim 1, I will test the effect of altered 5-HT1A receptor activity in various brain regions on escalation of cocaine intake with extended access and on cocaine-induced dysphoria-like states in rats by microinjecting agonists/antagonists or up/down-regulating receptors. In Specific Aim 2, I will examine changes in the level of 5-HT1A receptors and intracellular signaling molecules such as phosphokinase A, extracellular signal regulated kinase, etc in brain regions using western blot and immunohistochemistry. In Specific Aim 3, I will investigate the mechanisms underlying the suggested positive feedback relationship between mood disorders and cocaine addiction, focusing on the interaction between the 5-HT1A receptors and other brain stress/mood systems such as the corticotropine releasing factor and dynorphin systems. The outcome of the present proposal may provide further insight into mechanisms underlying the transition to drug addiction and may reveal new treatment opportunities.