The Role of Glial Monoamine Transporters in Cocaine-Induced Sensitization and Tolerance In the United States, there are 1.5 million people classified as dependent on or abusing cocaine. Cocaine inhibits dopamine reuptake by binding to high-affinity monoamine transporters thereby impairing removal of dopamine from the synapse. These increased dopamine levels have been associated with the rewarding effect reported by cocaine abusers. In the brain, glial cells surround neuronal processes and synapses and have multiple types of monoamine transporters, including the organic cation transporters (OCT) that are not blocked by cocaine. The general hypothesis of the present proposal is that activation of astrocytes by repeated administration of cocaine enhances their OCT- mediated monoamine uptake thus decreasing dopamine levels in response to a drug challenge and leading to the development of tolerance to cocaine. This hypothesis will be tested in the following two specific aims:
Specific Aim 1 : To determine the role of astrocytes in the development of behavioral sensitization and tolerance to cocaine. Our preliminary data suggest that inhibition of glial metabolism by the selective glial toxin fluorocitrate reduces tolerance to cocaine. We will determine if this effect is due to inhibition of monoamine uptake by the electrogenic transporters in astrocytes.
Specific Aim 2 : To determine the effect of repeated cocaine and monoamine administration on transporter currents and the protein levels of OCT transporters in cultured astrocytes and rat brain. We will determine if elevated levels of monoamines, particularly dopamine, up-regulate expression of the OCT transporters on astrocytes resulting in apparent behavioral tolerance to cocaine. In the present electrophysiological and western blot experiments, we will assess the effects of monoamines on OCT electrogenic currents and protein levels in both cultured astrocytes (i.e., a direct effect) and in brain slices after rats have become sensitized or tolerant to cocaine.
Specific Aim 3 : To determine the effects of repeated administration of cocaine on the accumulation in astrocytes of the fluorescent monoamine analog 4-(4-(dimethylaminp)-styryl)-Nmethylpyridinium;(ASP+). Using fluorescent imaging to study the accumulation of ASP+, a fluorescent substrate for DAT, NET and OCT in acutely separated astrocytes, we will measure the accumulation of ASP+ in acutely isolated astrocytes from control and cocaine treated animals.
Our preliminary data show that astrocytes are involved in the development of behavioral sensitization and/or tolerance to cocaine, probably due to their recently described cocaine insensitive monoamine transporters. We propose to study how cocaine affects the level of these transporters in astrocytes. Our studies could eventually lead to the development of novel drugs against the development of cocaine addiction - drugs that preferentially block cocaine insensitive monoamine transporters in astrocytes.
|Buchacz, Kate; Lau, Bryan; Jing, Yuezhou et al. (2016) Incidence of AIDS-Defining Opportunistic Infections in a Multicohort Analysis of HIV-infected Persons in the United States and Canada, 2000-2010. J Infect Dis 214:862-72|
|Fred-JimÃ©nez, Ruth M; Arroyo-Ãvila, MariangelÃ; Mayor, Ãngel M et al. (2016) Clinical Manifestations Associated with Overweight/Obesity in Puerto Ricans with Fibromyalgia Syndrome. J Obes 2016:1379289|
|MÃ©ndez-GonzÃ¡lez, Miguel P; Kucheryavykh, Yuriy V; Zayas-Santiago, Astrid et al. (2016) Novel KCNJ10 Gene Variations Compromise Function of Inwardly Rectifying Potassium Channel 4.1. J Biol Chem 291:7716-26|
|Santiago-RodrÃguez, Eduardo J; Mayor, Angel M; FernÃ¡ndez-Santos, Diana M et al. (2016) Profile of HIV-Infected Hispanics with Pancytopenia. Int J Environ Res Public Health 13:ijerph13010038|
|Inyushin, M; Kucheryavih, Yu; Kucheryavih, L et al. (2016) Superparamagnetic Properties of Hemozoin. Sci Rep 6:26212|
|Morales-Cruz, Moraima; Cruz-MontaÃ±ez, Alejandra; Figueroa, Cindy M et al. (2016) Combining Stimulus-Triggered Release and Active Targeting Strategies Improves Cytotoxicity of Cytochrome c Nanoparticles in Tumor Cells. Mol Pharm 13:2844-54|
|Rivera Rivera, Amilcar; Castillo-Pichardo, Linette; Gerena, Yamil et al. (2016) Anti-Breast Cancer Potential of Quercetin via the Akt/AMPK/Mammalian Target of Rapamycin (mTOR) Signaling Cascade. PLoS One 11:e0157251|
|Althoff, Keri N; Rebeiro, Peter F; Hanna, David B et al. (2016) A picture is worth a thousand words: maps of HIV indicators to inform research, programs, and policy from NA-ACCORD and CCASAnet clinical cohorts. J Int AIDS Soc 19:20707|
|Miranda-Diaz, Christine; Betancourt, Elba; Ruiz-Candelaria, Yelitza et al. (2016) Barriers for Compliance to Breast, Colorectal, and Cervical Screening Cancer Tests among Hispanic Patients. Int J Environ Res Public Health 13:ijerph13010021|
|Zueva, Lidia; Golubeva, Tatiana; Korneeva, Elena et al. (2016) Foveolar MÃ¼ller Cells of the Pied Flycatcher: Morphology and Distribution of Intermediate Filaments Regarding Cell Transparency. Microsc Microanal 22:379-86|
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