Rationale Several studies have demonstrated a correlation between extracellular glutamate concentration in the mesolimbic reward pathway and alcohol craving. Extracellular glutamate concentration is regulated by several glutamate transporters. Glial glutamate transporter 1 (GLT1) is one of them that regulates the majority of extracellular glutamate concentration. In addition cystine/glutamate antiporter (xCT) is another transporter that regulates extracellular glutamate. Objectives We focus in this study to determine the effects of ceftriaxone, β-lactam antibiotic, on glial proteins such as GLT1 isoforms, xCT, GLAST and several associated signaling pathways as well as ethanol intake in P rats. Additionally, to examine the onset of signaling pathways associated with GLT1 upregulation following ceftriaxone treatment, we tested two-day versus five-day daily dosing of ceftriaxone. Results Ceftriaxone treatment (100 mg/kg), two-day and five day, resulted in about five-fold reduction in ethanol intake by P rats. The reduction in ethanol intake was associated with significantly enhanced expression of GLT1, GLT1a, GLT1b, and xCT in the NAc and PFC of five-day ceftriaxone treated P rats. Two-day treated P rats showed marked changes in expression of these glutamate transporters in the PFC but not in the NAc. Importantly, ceftriaxone treated P rats (two-day and five-day) demonstrated enhanced phosphorylation of Akt and nuclear translocation of NFκB in the NAc and PFC compared to control animals. Conclusions These findings demonstrate that ceftriaxone treatment induced upregulation of GLT1, GLT1 isoforms, and xCT in association with activation of Akt-NFκB signaling pathway.

Emerging evidence indicates that dysfunctional glutamate neurotransmission is critical in the initiation and development of alcohol and drug dependence. Alcohol consumption induced downregulation of glutamate transporter 1 (GLT-1) as reported in previous studies from our laboratory. Glutamate is the major excitatory neurotransmitter in the brain, which acts via interactions with several glutamate receptors. Alcohol consumption interferes with the glutamatergic signal transmission by altering the functions of these receptors. Among the glutamatergic receptors involved in alcohol-drinking behavior are the metabotropic receptors such as mGluR1/5, mGluR2/3, and mGluR7, as well as the ionotropic receptors, NMDA and AMPA. Preclinical studies using agonists and antagonists implicate these glutamatergic receptors in the development of alcohol use disorder (AUD). Therefore, the purpose of this review is to discuss the neurocircuitry involving glutamate transmission in animals exposed to alcohol and further outline the role of metabotropic and ionotropic receptors in the regulation of alcohol-drinking behavior. This review provides ample information about the potential therapeutic role of glutamatergic receptors for the treatment of AUD.

Chronic ethanol consumption is known to downregulate expression of the major glutamate transporter 1 (GLT-1), which increases extracellular glutamate levels in subregions of the mesocorticolimbic reward pathway. While β-lactam antibiotics were initially identified as potent upregulators of GLT-1 expression, only ceftriaxone has been extensively studied in various drug addiction models. Therefore, in this study, chronic ethanol-drinking adult male alcohol-preferring (P) rats were treated with other β-lactam antibiotics, ampicillin, cefazolin or cefoperazone (100 mg/kg) once daily for five consecutive days to assess their effects on ethanol consumption. The results demonstrated that each compound significantly reduced ethanol intake compared to saline-treated control group. Importantly, each compound significantly upregulated both GLT-1 and pAKT expressions in the nucleus accumbens and prefrontal cortex compared to saline-treated control group. In addition, only cefoperazone significantly inhibited hepatic aldehyde dehydrogenase-2 enzyme activity. Moreover, these β-lactams exerted only a transient effect on sucrose drinking, suggesting specificity for chronically inhibiting ethanol reward in adult male P rats. Cerebrospinal fluid concentrations of ampicillin, cefazolin or cefoperazone have been confirmed using high-performance liquid chromatography. These findings demonstrate that multiple β–lactam antibiotics demonstrate efficacy in reducing alcohol consumption and appear to be potential therapeutic compounds for treating alcohol abuse and/or dependence. In addition, these results suggest that pAKT may be an important player in this effect, possibly through increased transcription of GLT-1.

Studies have shown that administration of the β-lactam antibiotic, ceftriaxone (CEF) attenuates ethanol consumption and cocaine seeking behavior as well as preventing ethanol-induced downregulation of glutamate transporter 1 (GLT-1) expression in central reward brain regions. However, it is not known if these effects are compound-specific. Therefore, the present study examined the effects of two other β-lactam antibiotics, amoxicillin (AMOX) and amoxicillin/clavulanate (Augmentin, AUG), on ethanol drinking, as well as GLT-1 and phosphorylated-AKT (pAKT) levels in the nucleus accumbens (Acb) and medial prefrontal cortex (mPFC) of alcohol-preferring (P) rats. P rats were exposed to free-choice of ethanol (15% and 30%) for five weeks and were given five consecutive daily i.p. injections of saline vehicle, 100 mg/kg AMOX or 100 mg/kg AUG. Both compounds significantly decreased ethanol intake and significantly increased GLT-1 expression in the Acb. AUG also increased GLT-1 expression in the mPFC. Results for changes in pAKT levels matched those for GLT-1, indicating that β-lactam antibiotic-induced reductions in ethanol intake are negatively associated with increases in GLT-1 and pAKT levels within two critical brains regions mediating drug reward and reinforcement. These findings add to a growing literature that pharmacological increases in GLT-1 expression are associated with decreases in ethanol intake and suggest that one mechanism mediating this effect may be increased phosphorylation of AKT. Thus, GLT-1 and pAKT may serve as molecular targets for the treatment of alcohol and drug abuse/dependence.