We have recently shown that upregulation of glutamate transporter 1 (GLT1) in the brain is associated in part with reduction in ethanol intake in alcohol-preferring (P) male rats. In this study, we investigated the effects of a synthetic compound, (R)-(−)-5-methyl-1-nicotinoyl-2-pyrazoline (MS-153), known to activate GLT1 on ethanol consumption as well as GLT1 expression and certain signaling pathways in P rats. P rats were given 24-hour concurrent access to 15% and 30% ethanol, water and food for five weeks. On week 6, P rats received MS-153 at a dose of 50 mg/kg (i.p.) or a vehicle (i.p.) for five consecutive days. We also tested the effect of MS-153 on daily sucrose (10%) intake. Our studies revealed a significant decrease in ethanol intake at the dose of 50 mg/kg MS-153 from Day 1 through Day 14. In addition, MS-153 at dose of 50 mg/kg did not induce any significant effect on sucrose intake. Importantly, we found that MS-153 upregulated the GLT1 level in the nucleus accumbens (NAc) but not in the prefrontal cortex (PFC). In accordance, we found upregulation of nuclear NFkB-65 level in NAc in MS-153-treated group, however, IkB was downregulated in MS-153-treated group in NAc. We did not find any changes in NFkB-65 and IkB levels in PFC. Interestingly, we revealed that p-Akt was downregulated in ethanol vehicle treated groups in the NAc; this downregulation was reversed by MS-153 treatment. We did not observe any significant differences in glutamate aspartate transporter (GLAST) expression among all groups. These findings reveal MS-153 as a GLT1 modulator that may have potential as a therapeutic drug for the treatment of alcohol dependence.

While health effects of conventional tobacco are well defined, data on vaping devices, including one of the most popular e-cigarettes which have high nicotine levels, are less established. Prior acute e-cigarette studies have demonstrated inflammatory and cardiopulmonary physiology changes while chronic studies have demonstrated extra-pulmonary effects, including neurotransmitter alterations in reward pathways. In this study we investigated the impact of inhalation of aerosols produced from pod-based, flavored e-cigarettes (JUUL) aerosols three times daily for 3 months on inflammatory markers in the brain, lung, heart, and colon. JUUL aerosol exposure induced upregulation of cytokine and chemokine gene expression and increased HMGB1 and RAGE in the nucleus accumbens in the central nervous system. Inflammatory gene expression increased in the colon, while gene expression was more broadly altered by e-cigarette aerosol inhalation in the lung. Cardiopulmonary inflammatory responses to acute lung injury with lipopolysaccharide were exacerbated in the heart. Flavor-specific findings were detected across these studies. Our findings suggest that daily e-cigarette use may cause neuroinflammation, which may contribute to behavioral changes and mood disorders. In addition, e-cigarette use may cause gut inflammation, which has been tied to poor systemic health, and cardiac inflammation, which leads to cardiovascular disease.

Accumulated evidence has focused on the use of natural polyphenolic compounds as nutraceuticals since they showed a wide range of bioactivities and exhibited protection against variety of age-related disorders. Polyphenols have variable potencies to interact, and hence alter the activities of various transporter proteins, many of them classified as anion transporting polypeptide-binding cassette transporters like multidrug resistance protein and p-glycoprotein. Some of the efflux transporters are, generally, linked with anticancer and antiviral drug resistance; in this context, polyphenols may be beneficial in modulating drug resistance by increasing the efficacy of anticancer and antiviral drugs. In addition, these effects were implicated to explain the influence of dietary polyphenols on drug efficacy as result of food-drug interactions. However, limited data are available about the influence of these components on uptake transporters. Therefore, the objective of this article is to review the potential efficacies of polyphenols in modulating the functional integrity of uptake transporter proteins, including those terminated the effect of neurotransmitters, and their possible influence in neuropharmacology.

Exposure to ethanol commonly manifests neuroinflammation. Beta (β)-lactam antibiotics attenuate ethanol drinking through upregulation of astroglial glutamate transporters, especially glutamate transporter-1 (GLT-1), in the mesocorticolimbic brain regions, including the nucleus accumbens (Acb). However, the effect of β-lactam antibiotics on neuroinflammation in animals chronically exposed to ethanol has not been fully investigated. In this study, we evaluated the effects of ampicillin/sulbactam (AMP/SUL, 100 and 200 mg/kg, i.p.) on ethanol consumption in high alcohol drinking (HAD1) rats. Additionally, we investigated the effects of AMP/SUL on GLT-1 and N-methyl-d-aspartate (NMDA) receptor subtypes (NR2A and NR2B) in the Acb core (AcbCo) and Acb shell (AcbSh). We found that AMP/SUL at both doses attenuated ethanol consumption and restored ethanol-decreased GLT-1 and NR2B expression in the AcbSh and AcbCo, respectively. Moreover, AMP/SUL (200 mg/kg, i.p.) reduced ethanol-increased high mobility group box 1 (HMGB1) and receptor for advanced glycation end-products (RAGE) expression in the AcbSh. Moreover, both doses of AMP/SUL attenuated ethanol-elevated tumor necrosis factor-alpha (TNF-α) in the AcbSh. Our results suggest that AMP/SUL attenuates ethanol drinking and modulates NMDA receptor NR2B subunits and HMGB1-associated pathways.