My immediate goal is to establish myself as an independent investigator. My long-term goal is to be a well-established researcher whose expertise contributed to our understanding of drug dependence. The present proposal for career development award is designed to elucidate the involvement of 5-HT1A receptors in the development of cocaine dependence. Drug dependence develops over frequent drug abuse. Thus, it is reasonable to examine changes in the neuronal systems with which a drug interacts to understand the pathology of drug dependence. One of the hypotheses is that the emergence of a negative emotional state during drug withdrawal plays a key role in the development of drug dependence. Cocaine stimulates the monoamine systems including serotonin (5-HT). Dysfunctional 5-HT1A receptors have been implicated in depression, anxiety and dysphoria, which are the major cocaine withdrawal symptoms in humans. However, the involvement of 5-HT1A receptors in cocaine dependence is not well understood. Our laboratory established a rodent model of drug self-administration with extended access, which mimics an increasing drug intake in dependent humans. Therefore, the present proposal explores the role of 5-HT1A receptors in cocaine dependence using this rodent model. The hypothesis is that changes in 5-HT1A receptors are associated with increased cocaine self-administration and the manifestation of cocaine withdrawal in rats with extended access.
Specific Aim 1 examines the role of 5-HT1A receptors in cocaine self-administration and cocaine withdrawal in rats with extended access using 5-HT1A receptor ligands.
Specific Aim 2 investigates time-dependent changes in 5-HT1A receptors in the extended amygdala and raphe nuclei in rats with extended access using Western blot and immunofluorescence.
Specific Aim 3 investigates the relationship between 5-HT1A receptors and comorbidity of depression and cocaine dependence using a rodent model of depression. The results from these Specific Aims will enhance our understanding of the neuronal mechanisms underlying cocaine dependence and serve as a foundation for independence in the applicant'research career.
Findings in the proposed research will enhance our understanding of the neural mechanisms underlying cocaine dependence and may serve as a guidance in the efforts to develop better pharmacotherapeutics.
|You, In-Jee; Wright, Sherie R; Garcia-Garcia, Alvaro L et al. (2016) 5-HT1A Autoreceptors in the Dorsal Raphe Nucleus Convey Vulnerability to Compulsive Cocaine Seeking. Neuropsychopharmacology 41:1210-22|
|Jang, Choon-Gon; Whitfield, Timothy; Schulteis, Gery et al. (2013) A dysphoric-like state during early withdrawal from extended access to methamphetamine self-administration in rats. Psychopharmacology (Berl) 225:753-63|
|Wee, Sunmee; Hicks, Martin J; De, Bishnu P et al. (2012) Novel cocaine vaccine linked to a disrupted adenovirus gene transfer vector blocks cocaine psychostimulant and reinforcing effects. Neuropsychopharmacology 37:1083-91|
|Wee, Sunmee; Vendruscolo, Leandro F; Misra, Kaushik K et al. (2012) A combination of buprenorphine and naltrexone blocks compulsive cocaine intake in rodents without producing dependence. Sci Transl Med 4:146ra110|
|Wee, Sunmee; Koob, George F (2010) The role of the dynorphin-kappa opioid system in the reinforcing effects of drugs of abuse. Psychopharmacology (Berl) 210:121-35|