β-Lactamase inhibitor, clavulanic acid, attenuates ethanol intake and increases glial glutamate transporters expression in alcohol preferring rats

Abstract

Studies from our laboratory showed that upregulation of glutamate transporter 1 (GLT-1) and cystine-glutamate exchanger (xCT) expression with ceftriaxone, β-lactam antibiotic, in the brain was associated with attenuation of ethanol consumption. In this study, we tested clavulanic acid, which is another β-lactam compound with negligible antimicrobial activity, on ethanol consumption and expression of GLT-1, xCT and glutamate aspartate transporter (GLAST) in male alcohol-preferring (P) rats. Clavulanic acid has the central β-lactam pharmacophore that is critical for the upregulation of GLT-1 and xCT expression. We found that clavulanic acid, at 5 mg/kg (i.p.) dose, significantly attenuated ethanol consumption and ethanol preference in P rats as compared to vehicle-treated group. This effect was associated with a significant increase in water intake in clavulanic acid treated group. Importantly, we found that clavulanic acid increased the expression of GLT-1 and xCT in nucleus accumbens. However, there was no effect of clavulanic acid on GLAST expression in the nucleus accumbens. Clavulanic acid treatment did not upregulate the expression of GLT-1, xCT and GLAST in prefrontal cortex. These findings revealed that clavulanic acid at 20–40 fold lower dose than ceftriaxone can attenuate ethanol consumption, in part through upregulation of GLT-1 and xCT expression in the nucleus accumbens. Thus, we suggest that clavulanic acid might be used as an alternative option to ceftriaxone to attenuate ethanol drinking behavior.

Ampicillin/Sulbactam Treatment Modulates NMDA Receptor NR2B Subunit and Attenuates Neuroinflammation and Alcohol Intake in Male High Alcohol Drinking Rats

“…Furthermore, our laboratory reported that AMP treatment for five days attenuated ethanol drinking behavior in P rats, an effect that was associated with upregulation of GLT-1 expression in the Acb [11]. In addition, β-lactamase inhibitors, clavulanic acid and SUL, showed ability to upregulate GLT-1 expression in rats [15,16,68]. In the present study, we found that nine weeks of ethanol consumption reduced the expression of GLT-1 in the AcbSh, but not in the AcbCo, and that combination of AMP and SUL attenuated this effect.…”

“…It is important to note that β-lactam antibiotics (e.g., ceftriaxone and ampicillin, AMP) increased GLT-1 expression in the Acb and attenuated ethanol-drinking behaviors [11][12][13][14]. Additionally, a β-lactamase inhibitor, clavulanic acid, decreased ethanol and cocaine-seeking behaviors, and increased the expression of GLT-1 in the Acb [15,16]. The increase in the synaptic glutamate concentrations is associated with alteration in certain glutamate receptors expression [17] as well as neuroinflammation [18].…”

Antioxidant and Antimicrobial Potential of New Azetidin-2-One of Ferulic Acid

“…Ferulic acid and its derivatives have proven a powerful antioxidant activity in response to free radicals, acting synergistically with other antioxidants. Due to its structure, ferulic acid presents the ability to interrupt the propagation of free radical chain reactions, provide attack sites for free radicals and ensure protection against lipid peroxidation [8,9,17,18]. On the other hand, the β-lactam heterocycles are substances which drew attention and interest of scientists for their potent antibacterial activity [1].…”

SLC Neurotransmitter Transporters as Therapeutic Targets for Alcohol Use Disorder: A Narrative Review

“…Lastly, given that the ability of β‐lactam antibiotics to induce EAAT2/GLT‐1 expression lies in their β‐lactam ring (Rothstein et al, 2005), other nonantibiotic β‐lactam compounds could also potentially treat AUD. Indeed, clavulanic acid significantly induced EAAT2/GLT‐1 (and xCT) expression in the nucleus accumbens and decreased EtOH intake and preference in P rats using a 2‐bottle choice paradigm (Hakami and Sari, 2017). Given its lack of antibiotic activity and ability to penetrate the blood–brain barrier, clavulanic acid could provide a superior treatment option for AUD over the other β‐lactam antibiotics explored.…”