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Effects of Modulating Glutamate Homeostasis in Methamphetamine and Alcohol Co-Abuse: Potential Therapeutic Targets

Althobaiti, Yusuf

Abstract Details

2016, Doctor of Philosophy (PhD), University of Toledo, Experimental Therapeutics.
Methamphetamine (METH) is one of the most commonly used psychostimulants that is highly co-abused with ethanol. The use of METH and ethanol can lead to deteriorating health problems and can alter the brain glutamate homeostasis. Glutamate homeostasis can be maintained by several glutamate transporters and receptors such as glutamate transporter type 1 (GLT-1), cystine-glutamate exchanger (xCT), glutamate aspartate transporter (GLAST), and group II metabotropic glutamate receptors (mGluR2/3). This project aimed to investigate the role of the key proteins involved in glutamate homeostasis using METH and ethanol co-abuse rat model. I showed an unprecedented evidence that repeated high doses of METH decreased GLT-1 expression in the nucleus accumbens (NAc) and prefrontal cortex (PFC) and increased body temperature. Interestingly, ethanol and METH were found to have an additive effect on the downregulation of GLT-1 expression in the NAc but not in the PFC. Ceftriaxone (CEF), a ß-lactam antibiotic known to upregulate GLT-1, significantly reversed METH-induced hyperthermia, restored GLT-1 expression, and increased xCT expression in the NAc and PFC. We then tested a non-antibiotic ß-lactam compound, clavulanic acid (CA) which can be administered orally, has better brain penetrability and is relatively safe. To test its activity on a METH and ethanol co-abuse rat model of drug dependence, we investigated the effect of CA on the reinstatement model of METH using conditioned place preference (CPP) paradigm as well as free choice ethanol drinking in alcohol preferring (P) rats. We further assessed the expression of GLT-1, xCT, GLAST, and mGluR2/3 in the NAc shell and core as well as dorsomedial PFC (dmPFC). We have found that the GLT-1 down-regulatory effect of METH and ethanol exposure in the NAc is specific to the shell subregion rather than the core. We showed for the first time that CA treatment blocked the reinstatement effect of METH, decreased ethanol intake, restored the expression of GLT-1 and xCT in the shell, and increased the expression of mGluR2/3 in the shell and dmPFC. We further investigated the mechanism of action of CA on METH induced reinstatement of CPP. The anti-reinstatement effect of seven-day CA treatment was completely blocked by pretreatment with the selective mGluR2/3 antagonist LY341495. Alternatively, a single dose pretreatment with CA did not block the reinstatement of METH CPP. Finally, we conducted an in vivo microdialysis study in freely moving P rats to assess glutamate release in the NAc shell or core following the reinstatement dose of METH. The reinstatement dose of METH increased glutamate release in the NAc shell, but not the NAc core, which was blocked by CA pre-treatment. Thus, restoring glutamate homeostasis following the development of METH dependence could be an effective therapeutic strategy to prevent relapse to drug seeking.
Youssef Sari (Committee Chair)
F. Scott Hall (Committee Member)
Zahoor Shah (Committee Member)
Wissam AbouAlaiwi (Committee Member)

Recommended Citations

Citations

  • Althobaiti, Y. (2016). Effects of Modulating Glutamate Homeostasis in Methamphetamine and Alcohol Co-Abuse: Potential Therapeutic Targets [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1480610727205278

    APA Style (7th edition)

  • Althobaiti, Yusuf . Effects of Modulating Glutamate Homeostasis in Methamphetamine and Alcohol Co-Abuse: Potential Therapeutic Targets. 2016. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1480610727205278.

    MLA Style (8th edition)

  • Althobaiti, Yusuf . "Effects of Modulating Glutamate Homeostasis in Methamphetamine and Alcohol Co-Abuse: Potential Therapeutic Targets." Doctoral dissertation, University of Toledo, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=mco1480610727205278

    Chicago Manual of Style (17th edition)