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The role of glutamate transporter1 and cystine-glutamate exchanger in cocaine and ethanol co-abuse: potential therapeutic targets

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2017, Doctor of Philosophy, University of Toledo, Experimental Therapeutics.
One of the most popular combinations of abused drugs among addicts is the concurrent use of cocaine and alcohol (ethanol). Previous studies intensively investigated the role of the dopaminergic system in cocaine and ethanol addiction. In addition, the glutamatergic system is another pathway that emerged as a key player in addiction and relapse and has been investigated intensively for the past decade. Glutamate is the main neurotransmitter in the central nervous system (CNS) that is involved in the process of long-term neuronal potentiation, which can help explain the tendency for relapse and persistence of behavioral characteristics of drugs of abuse even after the acute rewarding effects disappear. One of the main areas of investigation is the role of glial glutamate transporters in maintaining glutamate hemostasis and the effects of drugs of abuse on their expression. Glutamate transporter 1 (GLT-1) is responsible for clearing the majority of the extracellular glutamate from the synapse. Alongside GLT-1, the glutamate-aspartate transporter (GLAST) was found to help in maintaining glutamate homeostasis, albeit to a much lesser extent in the mesocorticolimbic pathway. The cystine- glutamine exchanger (xCT) is another glial glutamate transporter that is responsible for modulating basal glutamate concentrations. Importantly, the nucleus accumbens (NAc) and the prefrontal cortex (PFC) are two main brain regions within the mesocorticolimbic circuit that were investigated in regard to drug dependence. To the best of my knowledge, there is less known about the effects of cocaine and ethanol co-exposure on the glutamatergic system, including glial glutamate transporters expression in the mesocorticolimbic pathway, compared to the effects of either drug alone. The aim of this research project is to investigate the effects of cocaine and ethanol co-abuse on different glial glutamate transporters using young adult male alcohol preferring (P) rats in three different models that mimic different co-exposure conditions. We used ampicillin /sulbactam (AMP/SUL), a ß-lactam antibiotic known to upregulate the expression of certain glial glutamate transporters, to attenuate relapse-like drug seeking behavior. Repeated cocaine exposure (20 mg/kg, i.p) in male P rats exposed to voluntary home-cage ethanol drinking decreased ethanol intake. Co-exposure of cocaine and ethanol decreased the relative mRNA expression and the expression of GLT-1 protein in the NAc but not in the medial PFC (mPFC). Importantly, co-exposure of cocaine and ethanol decreased the relative mRNA expression of xCT in the NAc but not in the mPFC. Using the alcohol deprivation effect (ADE) model in P rats, repeated cocaine (20 mg/kg, i.p) induced a robust increase in relapse-like ethanol drinking behavior compared to saline-treated subjects, accompanied by a decrease in the expression of GLT-1 and xCT in the NAc core. AMP/SUL (100 mg/kg, i.p.) prevented the robust increase in relapse-like ethanol intake in this model, while AMP/SUL (200 mg/kg, i.p.) decreased the relapse-like ethanol drinking behavior and upregulated GLT-1 and xCT in the NAc core, shell and dorsomedial PFC (dmPFC). In a conditioned place preference model (CPP), cocaine-induced reinstatement was investigated in male P rats exposed to home-cage voluntary ethanol drinking. Cocaine and ethanol co-exposure acquired place preference and increased locomotor activity compared to ethanol-exposed rats. GLT-1 and xCT expression were both downregulated after co-exposure to cocaine and ethanol in the NAc core and the shell, but not in the dmPFC. AMP/SUL (200 mg/kg) attenuated cocaine-induced reinstatement, decreased locomotor activity, decreased ethanol intake and preference, and upregulated GLT-1 and xCT expression in the NAc core and shell as well as the dmPFC. GLAST expression was unchanged after ethanol and cocaine co-exposure or after AMP/SUL treatment. We also investigated cocaine-induced reinstatement in ethanol naive P rats. AMP/SUL treatment reduced cocaine-triggered reinstatement. This effect was associated with a decrease in locomotor activity. Moreover, GLT-1 and xCT were downregulated in the NAc core and shell but not in the dmPFC following cocaine-primed reinstatement. However, cocaine upregulated metabotropic glutamate receptor 1 (mGluR1) expression in the NAc core but not the NAc shell or the dmPFC. Importantly, AMP/SUL treatments normalized GLT-1 and xCT expression in the NAc core and shell; alternatively, the drug normalized mGluR1 expression in the NAc core only. Additionally, AMP/SUL upregulated GLT-1 and xCT in the dmPFC as compared to the untreated group. Taken together, it is evident that ethanol and cocaine co-exposure downregulated GLT-1 and xCT expression in different drugs co-exposure models and that modulating glial glutamate transporters may attenuate relapse-like behavior and craving. Thus, selected glial glutamate transporters could be potential therapeutic targets for the attenuation of reinstatement to cocaine seeking and relapse-like drinking behavior in polysubstance abusers.
Yousseff Sari, Dr. (Committee Chair)
Frank Hall, Dr. (Committee Member)
Zahoor Shah, Dr. (Committee Member)
Wissam AbouAlaiwi, Dr. (Committee Member)
372 p.

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Citations

  • Hammad, A. M. (2017). The role of glutamate transporter1 and cystine-glutamate exchanger in cocaine and ethanol co-abuse: potential therapeutic targets [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1503699629639942

    APA Style (7th edition)

  • Hammad, Alaa. The role of glutamate transporter1 and cystine-glutamate exchanger in cocaine and ethanol co-abuse: potential therapeutic targets. 2017. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=toledo1503699629639942.

    MLA Style (8th edition)

  • Hammad, Alaa. "The role of glutamate transporter1 and cystine-glutamate exchanger in cocaine and ethanol co-abuse: potential therapeutic targets." Doctoral dissertation, University of Toledo, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=toledo1503699629639942

    Chicago Manual of Style (17th edition)