Effects of ampicillin on cystine/glutamate antiporter and glutamate transporter 1 isoforms as well as ethanol drinking in male P rats

Abstract

Evidence demonstrated that glial cells, mainly astrocytes, regulate glutamate uptake, which is regulated by several glutamate transporters. Among these glutamate transporters, glutamate transporter 1 (GLT-1; its human homolog is excitatory amino acid transporter-2) is responsible for the majority of glutamate uptake by glial cells. Cystine-glutamate antiporter (xCT) is another glial protein critical in regulating glutamate transmission. Several studies from our laboratory demonstrated that attenuation of ethanol intkae was associated in part with upregulation of xCT and GLT suggesting the important role of these transporters in the treatment of ethanol dependence. We found recently that β-lactam antibiotic, ampicillin, upregulated GLT-1 expression in the prefrontal cortex (PFC) and nucleus accumbens (NAc) and consequently reduced ethanol intake in alcohol-preferring (P) rats. In this study, we investigated the effects of ampicillin on the expressions of xCT and GLT-1 isoforms (GLT-1a and GLT-1b) as well as on GLAST expression. We found that ampicillin reduced ethanol intake as compared to the saline (control)-treated group. In addition, we found that ampicillin induced upregulation of xCT, GLT-1a, and GLT-1b expressions in both the PFC and NAc, but had no effect on GLAST expression. Our findings provide significant role of ampicillin on upregulating xCT and GLT-1 isoforms expressions, might be suggested as possible tragets for the attenuation of ethanol consumption.

Effects of orally administered Augmentin on glutamate transporter 1, cystine-glutamate exchanger expression and ethanol intake in alcohol-preferring rats

“…This attenuation in ethanol consumption was associated with significant elevation of water intake. Similarly, several studies have reported that reduction in ethanol consumption was associated with an increase of water intake (24, 27, 46). We suggest this increase in water intake is a compensatory mechanism for the reduction in ethanol intake in order to maintain the fluid intake in P rat model.…”

Metabotropic and ionotropic glutamate receptors as potential targets for the treatment of alcohol use disorder

“…Glutamatergic projections from the AMG and HPC to the PFC and NAc establish and provide previously learned information associated with experience, further influencing complex behavioral responses (Kalivas and Volkow, 2005). Interestingly, it is also found that the glutamatergic system plays a critical role in alcohol-associated dependence, including chronic alcohol seeking and relapse (Alasmari et al, 2015a; Bäckström and Hyytiä, 2004; Dahchour et al, 1998; Krupitsky et al, 2007a; Nagy, 2008; Rossetti et al, 1999). …”

“…This later study suggests that glutamatergic innervation in the VTA plays a crucial role in glutamate-stimulated dopamine release. The dysfunctional connectivity and alteration in glutamatergic transmission are associated with chronic alcohol seeking, relapse, craving, tolerance and withdrawal (Alasmari et al, 2015a; Bäckström and Hyytiä, 2004; Dahchour et al, 1998; Krupitsky et al, 2007a; Nagy, 2008; Rossetti et al, 1999), which provide evidence of the involvement of glutamate transmission in the NAc and VTA in alcohol-seeking behavior. The apparent role of glutamate in the development of AUD suggests glutamatergic system as a potential therapeutic target to block the reinforcing effects of alcohol as well as to attenuate chronic and reinstatement of alcohol-seeking behavior (Alasmari et al, 2016; Bäckström and Hyytiä, 2004; Besheer et al, 2010; Qrunfleh et al, 2013).…”

Targeting glutamate homeostasis for potential treatment of nicotine dependence

“…Recent studies from our lab and others have demonstrated the important role of glutamate transporters. GLT-1 and xCT have been suggested as key players in ethanol intake (Aal-Aaboda et al, 2015, Alasmari et al, 2015). Thus, upregulation of these transporters by ceftriaxone, a β-lactam antibiotic known to upregulate GLT-1, was associated with attenuation of relapse to ethanol and cocaine seeking (Knackstedt et al, 2010, Qrunfleh et al, 2013, Alhaddad et al, 2014a).…”