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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Minority Health and Health Disparities (NIMHD)
Type
Research Centers in Minority Institutions Award (G12)
Project #
5G12MD007583-28
Application #
8573408
Study Section
Special Emphasis Panel (ZRR1-RI-B)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
28
Fiscal Year
2013
Total Cost
$122,405
Indirect Cost
$40,649
Name
Universidad Central Del Caribe
Department
Type
DUNS #
090534694
City
Bayamon
State
PR
Country
United States
Zip Code
00960
Huertas, Adriana; Wessinger, William D; Kucheryavykh, Yuri V et al. (2015) Quinine enhances the behavioral stimulant effect of cocaine in mice. Pharmacol Biochem Behav 129:26-33
Ferchmin, P A; Andino, Myrna; Reyes Salaman, Rebeca et al. (2014) 4R-cembranoid protects against diisopropylfluorophosphate-mediated neurodegeneration. Neurotoxicology 44:80-90
Althoff, Keri N; Rebeiro, Peter; Brooks, John T et al. (2014) Disparities in the quality of HIV care when using US Department of Health and Human Services indicators. Clin Infect Dis 58:1185-9
Zayas-Santiago, Astrid; Agte, Silke; Rivera, Yomarie et al. (2014) Unidirectional photoreceptor-to-Müller glia coupling and unique K+ channel expression in Caiman retina. PLoS One 9:e97155
Ríos, Grissel; Estrada, Marcos; Mayor, Angel M et al. (2014) Factors associated with tender point count in Puerto Ricans with fibromyalgia syndrome. P R Health Sci J 33:112-6
Rebeiro, Peter F; Horberg, Michael A; Gange, Stephen J et al. (2014) Strong agreement of nationally recommended retention measures from the Institute of Medicine and Department of Health and Human Services. PLoS One 9:e111772
Schikorski, Thomas (2014) Readily releasable vesicles recycle at the active zone of hippocampal synapses. Proc Natl Acad Sci U S A 111:5415-20
Skatchkov, Serguei N; Woodbury-Fariña, Michel A; Eaton, Misty (2014) The role of glia in stress: polyamines and brain disorders. Psychiatr Clin North Am 37:653-78
Santiago-Rodríguez, Eduardo J; Mayor, Angel M; Fernández-Santos, Diana M et al. (2014) Anemia in a cohort of HIV-infected Hispanics: prevalence, associated factors and impact on one-year mortality. BMC Res Notes 7:439
Sanabria-Rios, David J; Rivera-Torres, Yaritza; Maldonado-Dominguez, Gamalier et al. (2014) Antibacterial activity of 2-alkynoic fatty acids against multidrug-resistant bacteria. Chem Phys Lipids 178:84-91

Showing the most recent 10 out of 18 publications