Effects of MS-153 on chronic ethanol consumption and GLT1 modulation of glutamate levels in male alcohol-preferring rats

• Published in: Frontiers in behavioral neuroscience Vol. 8; p. 366
• Main Authors: Alhaddad, Hasan, Kim, Nathaniel T, Aal-Aaboda, Munaf, Althobaiti, Yusuf S, Leighton, James, Boddu, Sai H S, Wei, Yangjie, Sari, Youssef
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Research Foundation 30.10.2014; Frontiers Media S.A
• Subjects: Addictive behaviors; AKT protein; Alcohol; alcohol dependence; Antibiotics; Behavior; Calibration; Cocaine; Drug dependence; EAAT2; Ethanol; GLT1; Glutamate; Glutamic acid transporter; Laboratory animals; MS-153; Neuroscience; Neurosciences; NF-κB protein; Nucleus accumbens; P rats; Pharmaceutical sciences; Pharmacy; Prefrontal cortex; Substance abuse treatment; Sucrose; United States > US; EAAT2; GLT1; MS-153; P rats; alcohol dependence; glutamate
• ISSN: 1662-5153; 1662-5153
• DOI: 10.3389/fnbeh.2014.00366

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-h concurrent access to 15 and 30% ethanol, water and food for 5 weeks. On week 6, P rats received MS-153 at a dose of 50 mg/kg (i.p.) or a vehicle (i.p.) for 5 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 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, IkBα was downregulated in MS-153-treated group in NAc. We did not find any changes in NFkB-65 and IkBα 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.