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

Alhaddad H, Kim NT, Aal-Aaboda M, Althobaiti YS, Leighton J, Boddu SH, Wei Y, Sari Y - Front Behav Neurosci (2014)

Bottom Line: In addition, MS-153 at dose of 50 mg/kg did not induce any significant effect on sucrose intake.We did not find any changes in NFkB-65 and IkBα levels in PFC.We did not observe any significant differences in glutamate aspartate transporter (GLAST) expression among all groups.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Toledo, OH, USA.

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.

No MeSH data available.


Related in: MedlinePlus

Effects of MS-153 (50 mg/kg) on GLAST expression in PFC and NAc. (A,C) Immunoblots for GLAST and GAPDH, which was used as a control loading protein, in the PFC and NAc, respectively. (B,D) Quantitative analysis did not reveal any significant differences in the ratio of GLAST/GAPDH among all groups in PFC and NAc, respectively. Values shown as means ± s.e.m. (n = 5 for each group).
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Figure 11: Effects of MS-153 (50 mg/kg) on GLAST expression in PFC and NAc. (A,C) Immunoblots for GLAST and GAPDH, which was used as a control loading protein, in the PFC and NAc, respectively. (B,D) Quantitative analysis did not reveal any significant differences in the ratio of GLAST/GAPDH among all groups in PFC and NAc, respectively. Values shown as means ± s.e.m. (n = 5 for each group).

Mentions: We further tested whether MS-153 affects another astroglial transporter such as GLAST, which is co-expressed with GLT1. Thus, we examined the effects of MS-153 on GLAST level in both PFC and NAc. One-Way ANOVA analyses did not reveal any significant differences between all tested groups in PFC (Figures 11A,B) [F(2, 14) = 0.27, p = 0.76], and in NAc (Figures 11C,D) [F(2, 14) = 0.64, p = 0.54].


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

Alhaddad H, Kim NT, Aal-Aaboda M, Althobaiti YS, Leighton J, Boddu SH, Wei Y, Sari Y - Front Behav Neurosci (2014)

Effects of MS-153 (50 mg/kg) on GLAST expression in PFC and NAc. (A,C) Immunoblots for GLAST and GAPDH, which was used as a control loading protein, in the PFC and NAc, respectively. (B,D) Quantitative analysis did not reveal any significant differences in the ratio of GLAST/GAPDH among all groups in PFC and NAc, respectively. Values shown as means ± s.e.m. (n = 5 for each group).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214358&req=5

Figure 11: Effects of MS-153 (50 mg/kg) on GLAST expression in PFC and NAc. (A,C) Immunoblots for GLAST and GAPDH, which was used as a control loading protein, in the PFC and NAc, respectively. (B,D) Quantitative analysis did not reveal any significant differences in the ratio of GLAST/GAPDH among all groups in PFC and NAc, respectively. Values shown as means ± s.e.m. (n = 5 for each group).
Mentions: We further tested whether MS-153 affects another astroglial transporter such as GLAST, which is co-expressed with GLT1. Thus, we examined the effects of MS-153 on GLAST level in both PFC and NAc. One-Way ANOVA analyses did not reveal any significant differences between all tested groups in PFC (Figures 11A,B) [F(2, 14) = 0.27, p = 0.76], and in NAc (Figures 11C,D) [F(2, 14) = 0.64, p = 0.54].

Bottom Line: In addition, MS-153 at dose of 50 mg/kg did not induce any significant effect on sucrose intake.We did not find any changes in NFkB-65 and IkBα levels in PFC.We did not observe any significant differences in glutamate aspartate transporter (GLAST) expression among all groups.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, College of Pharmacy and Pharmaceutical Sciences, University of Toledo Toledo, OH, USA.

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.

No MeSH data available.


Related in: MedlinePlus