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

Hasan Alhaddad,Nathaniel T Kim,Yangjie Wei,Munaf Aal-Aaboda,James Leighton,Youssef Sari,Yusuf S Althobaiti,Sai H S Boddu

doi:10.3389/fnbeh.2014.00366

Hasan Alhaddad, Nathaniel T Kim + Show 6 more

Open Access

https://doi.org/10.3389/fnbeh.2014.00366

Copy DOI

Abstract

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.

Highlights

Deficits in glutamate uptake have been suggested to impair neurocircuits involved in drug abuse and drug-seeking behavior, affecting many aspects of neuroplasticity associated with ethanol and drug addiction
We found that MS-153 reduced ethanol intake dramatically
MS-153 had no effect on sucrose intake, which indicates that the action of this drug is specific to ethanol intake and does not affect sucrose as an appetitive control, drinking-motivated behavior

Summary

Introduction

Deficits in glutamate uptake have been suggested to impair neurocircuits involved in drug abuse and drug-seeking behavior, affecting many aspects of neuroplasticity associated with ethanol and drug addiction. In vitro and in vivo studies have demonstrated that ethanol exposure affects glutamate transport (Smith, 1997; Smith and Weiss, 1999; Othman et al, 2002; Melendez et al, 2005). Studies have shown that ceftriaxone, a β-lactam antibiotic, has an upregulatory effects in GLT1 levels (Rothstein et al, 2005; Miller et al, 2008; Sari et al, 2009, 2010). Studies from our lab and others have demonstrated that ceftriaxone attenuated cue-induced reinstatement of cocaine-seeking behavior (Sari et al, 2009; Knackstedt et al, 2010). The behavioral effects of ceftriaxone were associated with upregulation of GLT1 in the prefrontal cortex (PFC) and nucleus accumbens (NAc)

Objectives

Results

Conclusion