Amoxicillin and amoxicillin/clavulanate reduce ethanol intake and increase GLT-1 expression as well as AKT phosphorylation in mesocorticolimbic regions

Abstract

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.

Binge ethanol withdrawal: Effects on post-withdrawal ethanol intake, glutamate–glutamine cycle and monoamine tissue content in P rat model

“…In contrast to this present finding, we previously reported that five weeks of voluntary ethanol drinking downregulated GLT-1 expression in NAc, but not in mPFC (Sari and Sreemantula, 2012, Goodwani et al, 2015). This discrepancy might be attributed to the use of binge ethanol exposure and severe withdrawal vs five weeks of voluntary ethanol drinking.…”

Modulatory effects of Ampicillin/Sulbactam on glial glutamate transporters and metabotropic glutamate receptor 1 as well as reinstatement to cocaine-seeking behavior

“…These results are in agreement with previous results from our lab showing that different β-lactam antibiotics upregulated GLT-1 and xCT in the NAc and PFC and consequently attenuated alcohol drinking (18, 21, 74). Moreover, previous studies from our lab reported that β-lactam antibiotics increased GLT-1 and xCT, in part by increasing the expression of nuclear factor kappa-B and phospho-AKT in the NAc (20, 86, 87). This suggests that these signaling pathways could be a possible mechanism for β-lactam antibiotic to upregulate these glial glutamate transporters.…”

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

“…Our lab has shown that chronic ethanol consumption decreases the expression of GLT-1, GLT-1 isoforms and xCT (Aal-Aaboda et al, 2015; Alhaddad et al, 2014a; Alhaddad et al, 2014b; Hakami et al, 2016; Sari and Sreemantula, 2012). We have also shown that pharmacological upregulation of GLT-1 and xCT attenuated ethanol-drinking behaviors, including continuous and relapse ethanol drinking (Alasmari et al, 2015a; Alhaddad et al, 2014a; Alhaddad et al, 2014b; Goodwani et al, 2015; Rao and Sari, 2014; Rao et al, 2015). Ceftriaxone, a β-lactam antibiotic, was able to decrease ethanol intake, an effect was associated with upregulation of GLT-1 expression in central reward brain regions (Rao and Sari, 2014).…”