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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

(A) Effects of MS-153 treatment and post-treatment on daily ethanol intake in male P rats exposed to 5 weeks of free choice of ethanol and water. Vehicle (n = 8), and MS-153 50 mg/kg (n = 8). Statistical analyses demonstrated a significant decrease in ethanol intake with the MS-153 (50 mg/kg, i.p.) treated group from Day 1 (24 h after the first i.p. injection) through Day 14 (10 days after the last injection) as compared to ethanol vehicle group. (B) Effects of MS-153 treatment on water intake in P rats exposed to 5 weeks of free choice of ethanol and water. Statistical analyses demonstrated a significant increase in water consumption on days 3–8. (C) Effects of MS-153 treatment on body weight. Statistical analyses did not demonstrate any significant effects of MS-153 on body weight. Values shown as means ± s.e.m. (*p < 0.05; **p < 0.01).
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Figure 4: (A) Effects of MS-153 treatment and post-treatment on daily ethanol intake in male P rats exposed to 5 weeks of free choice of ethanol and water. Vehicle (n = 8), and MS-153 50 mg/kg (n = 8). Statistical analyses demonstrated a significant decrease in ethanol intake with the MS-153 (50 mg/kg, i.p.) treated group from Day 1 (24 h after the first i.p. injection) through Day 14 (10 days after the last injection) as compared to ethanol vehicle group. (B) Effects of MS-153 treatment on water intake in P rats exposed to 5 weeks of free choice of ethanol and water. Statistical analyses demonstrated a significant increase in water consumption on days 3–8. (C) Effects of MS-153 treatment on body weight. Statistical analyses did not demonstrate any significant effects of MS-153 on body weight. Values shown as means ± s.e.m. (*p < 0.05; **p < 0.01).

Mentions: We next examined the long-lasting effect of MS-153 on ethanol drinking behavior at the dose 50 mg/kg. GLM repeated measures revealed a significant main effect of Day [F(1, 14) = 19.839; p < 0.0001] and a significant Treatment × Day interaction [F(1, 14) = 2.814; p < 0.01]. One-Way ANOVA revealed a significant reduction in ethanol intake in the MS-153 50 group compared to the ethanol vehicle group from Days 1 to 14 (p < 0.01) (Figure 4A). Furthermore, GLM repeated measures demonstrated a significant main effect of Day on water intake [F(1, 14) = 3.512, p < 0.0001] and a significant Treatment × Day interaction [F(1, 14) = 2.39, p < 0.01]. One-Way ANOVA demonstrated a significant increase in water intake in the MS-153 50 group compared to the ethanol vehicle group on Days 3–8 (p < 0.05, p < 0.05) (Figure 4B). In addition, GLM repeated measures demonstrated a significant main effect of Day on body weight [F(1, 14) = 5.147, p < 0.0001] and a significant Treatment × Day interaction [F(1, 14) = 19.618, p < 0.0001]. However, One-Way ANOVA did not reveal a significant difference in body weight between the ethanol vehicle and ethanol MS-153 50 groups (Figure 4C).


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)

(A) Effects of MS-153 treatment and post-treatment on daily ethanol intake in male P rats exposed to 5 weeks of free choice of ethanol and water. Vehicle (n = 8), and MS-153 50 mg/kg (n = 8). Statistical analyses demonstrated a significant decrease in ethanol intake with the MS-153 (50 mg/kg, i.p.) treated group from Day 1 (24 h after the first i.p. injection) through Day 14 (10 days after the last injection) as compared to ethanol vehicle group. (B) Effects of MS-153 treatment on water intake in P rats exposed to 5 weeks of free choice of ethanol and water. Statistical analyses demonstrated a significant increase in water consumption on days 3–8. (C) Effects of MS-153 treatment on body weight. Statistical analyses did not demonstrate any significant effects of MS-153 on body weight. Values shown as means ± s.e.m. (*p < 0.05; **p < 0.01).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: (A) Effects of MS-153 treatment and post-treatment on daily ethanol intake in male P rats exposed to 5 weeks of free choice of ethanol and water. Vehicle (n = 8), and MS-153 50 mg/kg (n = 8). Statistical analyses demonstrated a significant decrease in ethanol intake with the MS-153 (50 mg/kg, i.p.) treated group from Day 1 (24 h after the first i.p. injection) through Day 14 (10 days after the last injection) as compared to ethanol vehicle group. (B) Effects of MS-153 treatment on water intake in P rats exposed to 5 weeks of free choice of ethanol and water. Statistical analyses demonstrated a significant increase in water consumption on days 3–8. (C) Effects of MS-153 treatment on body weight. Statistical analyses did not demonstrate any significant effects of MS-153 on body weight. Values shown as means ± s.e.m. (*p < 0.05; **p < 0.01).
Mentions: We next examined the long-lasting effect of MS-153 on ethanol drinking behavior at the dose 50 mg/kg. GLM repeated measures revealed a significant main effect of Day [F(1, 14) = 19.839; p < 0.0001] and a significant Treatment × Day interaction [F(1, 14) = 2.814; p < 0.01]. One-Way ANOVA revealed a significant reduction in ethanol intake in the MS-153 50 group compared to the ethanol vehicle group from Days 1 to 14 (p < 0.01) (Figure 4A). Furthermore, GLM repeated measures demonstrated a significant main effect of Day on water intake [F(1, 14) = 3.512, p < 0.0001] and a significant Treatment × Day interaction [F(1, 14) = 2.39, p < 0.01]. One-Way ANOVA demonstrated a significant increase in water intake in the MS-153 50 group compared to the ethanol vehicle group on Days 3–8 (p < 0.05, p < 0.05) (Figure 4B). In addition, GLM repeated measures demonstrated a significant main effect of Day on body weight [F(1, 14) = 5.147, p < 0.0001] and a significant Treatment × Day interaction [F(1, 14) = 19.618, p < 0.0001]. However, One-Way ANOVA did not reveal a significant difference in body weight between the ethanol vehicle and ethanol MS-153 50 groups (Figure 4C).

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