Alcohol (EtOH) abuse and dependence continue to be significant public health problems. Thus, a better understanding of their neurobiology will facilitate the development of interventions targeting prevention and/or treatment of these major health issues. Emerging evidence indicates that many aspects of EtOH and drug dependence involve changes in glutamate transmission. Because glutamate transporter 1 (GLT1) is responsible for the uptake of the majority of extracellular glutamate, we tested the hypothesis that increased GLT1 function would attenuate EtOH consumption in alcohol-preferring rats (P rats). After P rats had been chronically exposed to a free choice of EtOH (15 and 30%) for five weeks, they were administered ceftriaxone (i.p.), a beta-lactam antibiotic known to elevate GLT1 expression, for five consecutive days. We found that ceftriaxone-treated P rats showed a reduction in EtOH intake for the duration of treatment as compared to rats that received a saline vehicle. The long-term effects of ceftriaxone, however, are unknown. Here, we will test the long-term effects of ceftriaxone and other drugs (GPI-1046 and MS-153) known to activate GLT1 in the attenuation of EtOH intake at two different time points of chronic EtOH exposure in P rats. We will also investigate the effects of GLT1 activation in EtOH-drinking behavior in Wistar rats as comparison control groups. Our working hypothesis in aim 1 is that an increase in GLT1 function, via up- regulation or activation, attenuates EtOH consumption in both P and Wistar rats. The EtOH deprivation effect, which we will employ, has been used to assess relapse-like behavior in P rats.
In aim 2, our working hypothesis is that an increase in GLT1 function during withdrawal periods will reduce relapse-like behavior when animals are re-exposed to EtOH. The lowest tested dose of ceftriaxone (25 mg/kg), which did not show an increase in GLT1 expression, was also effective in reducing EtOH intake. These findings suggest that ceftriaxone may have other pharmacological effects on GLT1 or may act by another mechanism (a functional increase may involve a change in one of several mechanisms). Thus, we propose in aim 3 to determine the signaling pathways involving ceftriaxone or GPI-1046 in up-regulation of GLT1 expression. Moreover, we aim to determine the molecular mechanisms of action of ceftriaxone, GPI-1046 and MS-153, which may involve activation of GLT1 function through phosphorylation of key proteins. The findings generated from this proposal will provide ample information about the role of GLT1 in the regulation of EtOH consumption and will pave the path toward finding a potential therapeutic target for alcohol addiction.

Public Health Relevance

The goal of this proposal is to investigate the role of glutamate transporter, a neurotransmitter transporter, in alcohol dependence. This chemical transporter plays an important role in alcohol-drinking behavior. From this study, we aim to provide ample information about the role of this transporter in the reduction of alcohol consumption and hope to pave the path toward potential therapeutic targets for alcohol dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA019458-03
Application #
8461673
Study Section
Neurotoxicology and Alcohol Study Section (NAL)
Program Officer
Cui, Changhai
Project Start
2011-05-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$219,420
Indirect Cost
$72,945
Name
University of Toledo
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
Alasmari, Fawaz; Al-Rejaie, Salim S; AlSharari, Shakir D et al. (2016) Targeting glutamate homeostasis for potential treatment of nicotine dependence. Brain Res Bull 121:1-8
Alasmari, Fawaz; Rao, P S S; Sari, Youssef (2016) Effects of cefazolin and cefoperazone on glutamate transporter 1 isoforms and cystine/glutamate exchanger as well as alcohol drinking behavior in male alcohol-preferring rats. Brain Res 1634:150-7
Das, Sujan C; Althobaiti, Yusuf S; Alshehri, Fahad S et al. (2016) Binge ethanol withdrawal: Effects on post-withdrawal ethanol intake, glutamate-glutamine cycle and monoamine tissue content in P rat model. Behav Brain Res 303:120-5
Sari, Youssef; Toalston, Jamie E; Rao, P S S et al. (2016) Effects of ceftriaxone on ethanol, nicotine or sucrose intake by alcohol-preferring (P) rats and its association with GLT-1 expression. Neuroscience 326:117-25
Alshehri, Fahad S; Althobaiti, Yusuf S; Sari, Youssef (2016) Effects of Administered Ethanol and Methamphetamine on Glial Glutamate Transporters in Rat Striatum and Hippocampus. J Mol Neurosci :
Althobaiti, Yusuf S; Alshehri, Fahad S; Almalki, Atiah H et al. (2016) Effects of Ceftriaxone on Glial Glutamate Transporters in Wistar Rats Administered Sequential Ethanol and Methamphetamine. Front Neurosci 10:427
Althobaiti, Yusuf S; Sari, Youssef (2016) Alcohol Interactions with Psychostimulants: An Overview of Animal and Human Studies. J Addict Res Ther 7:
Patel, Nachiket; Lalwani, Darshan; Gollmer, Steven et al. (2016) Development and evaluation of a calcium alginate based oral ceftriaxone sodium formulation. Prog Biomater 5:117-133
Rao, P S S; Saternos, Hannah; Goodwani, Sunil et al. (2015) Effects of ceftriaxone on GLT1 isoforms, xCT and associated signaling pathways in P rats exposed to ethanol. Psychopharmacology (Berl) 232:2333-42
Alasmari, Fawaz; Abuhamdah, Sawsan; Sari, Youssef (2015) Effects of ampicillin on cystine/glutamate antiporter and glutamate transporter 1 isoforms as well as ethanol drinking in male P rats. Neurosci Lett 600:148-52

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