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Pharmacological Studies of Compounds Targeting Glutamate Transporter 1 for the Attenuation of Alcohol-Drinking Behavior in Alcohol Preferring Rats

Alhaddad, Hasan
http://orcid.org/0000-0002-3633-5705
http://rave.ohiolink.edu/etdc/view?acc_num=mco1370438659

Abstract Details

2013, Master of Science in Pharmaceutical Science (MSP), University of Toledo, College of Pharmacy.
Alcoholism is a disorder involving chronic and progressive alcohol intake which leads to mental, physical and social problems. Drinking alcohol has an impact on various neurotransmitter systems within the brain. For example, alcohol self-administration increases dopamine and glutamate neurotransmission in central reward brain regions such as prefrontal cortex (PFC) and nucleus accumbens (NAC). Evidence demonstrated that glutamatergic system is implicated in the development of alcohol dependence. Extracellular glutamate levels are regulated by a number of glutamate transporters. Among these transporters, glutamate transporter 1 (GLT-1) is responsible for clearance of more than 90 % of the extracellular glutamate. Studies from our lab have shown that ceftriaxone (CEF), a beta lactam antibiotic known to upregulate GLT-1 level, reduced ethanol-drinking behavior in alcohol preferring (P) rats in both chronic and relapse-like ethanol-drinking behavior paradigms. In this study, the differential effects of CEF on GLT-1 isoforms (GLT-1a and GLT-1b), cystine-glutamate antiporter (xCT) and glutamate-aspartate transporter (GLAST) were examined (using Western blot) in naive (water) control, saline vehicle control (relapse-like ethanol), CEF (100 mg/kg, i.p.) treated P rat groups. Furthermore, we examined the effect of MS-153, a novel neuroprotective agent, on ethanol consumption and GLT1 expression and its signaling pathway in naive (water) control, saline vehicle control (ethanol), MS-153 (20 and 50 mg/kg, i.p.) treated P rats. Our results showed that CEF treatment attenuated relapse-like ethanol-drinking behavior in P rats. This attenuation was associated, in part, with up-regulation in the levels of GLT-1a, GLT-1b, as well as xCT in PFC and NAC. However, we did not observe any significant change in GLAST level between all groups. Alternatively, we found that MS-153 significantly reduced ethanol intake in P rats at dose-dependent manner. Importantly, MS-153 up-regulated GLT-1 levels in NAC and amygdala (AMG) but not in PFC. Furthermore, we found that up-regulation of GLT-1 level was associated with up-regulation of translocated Nuclear Factor kappa B (NFkB) and reduction in cytosolic IkB-alpha levels. Our data showed for the first time that a novel compound, MS-153, targeting GLT-1 had the beneficiary effect for attenuating ethanol intake. Together, our findings demonstrated GLT-1 as a potential therapeutic target for treatment of alcohol dependence.
Youssef Sari, Ph.D. (Committee Chair)
Ming-Cheh Liu, Ph.D. (Committee Member)
Zahoor Shah, Ph.D. (Committee Member)
Neurosciences; Pharmacology; Pharmacy Sciences

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Citations

  • Alhaddad, H. (2013). Pharmacological Studies of Compounds Targeting Glutamate Transporter 1 for the Attenuation of Alcohol-Drinking Behavior in Alcohol Preferring Rats [Master's thesis, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1370438659

    APA Style (7th edition)

  • Alhaddad, Hasan. Pharmacological Studies of Compounds Targeting Glutamate Transporter 1 for the Attenuation of Alcohol-Drinking Behavior in Alcohol Preferring Rats. 2013. University of Toledo, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1370438659.

    MLA Style (8th edition)

  • Alhaddad, Hasan. "Pharmacological Studies of Compounds Targeting Glutamate Transporter 1 for the Attenuation of Alcohol-Drinking Behavior in Alcohol Preferring Rats." Master's thesis, University of Toledo, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=mco1370438659

    Chicago Manual of Style (17th edition)

mco1370438659
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This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.