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Neuronal Nicotinic Acetylcholine Receptor Modulators Reduce Sugar Intake.

Shariff M, Quik M, Holgate J, Morgan M, Patkar OL, Tam V, Belmer A, Bartlett SE - PLoS ONE (2016)

Bottom Line: We report that varenicline, an FDA-approved nicotinic acetylcholine receptor (nAChR) partial agonist that modulates dopamine in the mesolimbic reward pathway of the brain, significantly reduces sucrose consumption, especially in a long-term consumption paradigm.Furthermore, we show that long-term sucrose consumption increases α4β2 * and decreases α6β2* nAChRs in the nucleus accumbens, a key brain region associated with reward.Taken together, our results suggest that nAChR drugs such as varenicline may represent a novel treatment strategy for reducing sugar consumption.

View Article: PubMed Central - PubMed

Affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology at Translational Research Institute, Brisbane, Australia.

ABSTRACT
Excess sugar consumption has been shown to contribute directly to weight gain, thus contributing to the growing worldwide obesity epidemic. Interestingly, increased sugar consumption has been shown to repeatedly elevate dopamine levels in the nucleus accumbens (NAc), in the mesolimbic reward pathway of the brain similar to many drugs of abuse. We report that varenicline, an FDA-approved nicotinic acetylcholine receptor (nAChR) partial agonist that modulates dopamine in the mesolimbic reward pathway of the brain, significantly reduces sucrose consumption, especially in a long-term consumption paradigm. Similar results were observed with other nAChR drugs, namely mecamylamine and cytisine. Furthermore, we show that long-term sucrose consumption increases α4β2 * and decreases α6β2* nAChRs in the nucleus accumbens, a key brain region associated with reward. Taken together, our results suggest that nAChR drugs such as varenicline may represent a novel treatment strategy for reducing sugar consumption.

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Long-term sucrose intake (12 weeks) increases α4(nonα6)β2* nAChR and decreases α6β2* nAChR levels in rat nucleus accumbens (NAc).Quantitative analyses of α4(nonα6)β2* nAChR binding using 125I-Epibatidine binding in the absence and presence of α-CtxMII show show a significant increase in α4(nonα6)β2* nAChRs (A and B) with a decrease in α6β2* nAChRs (C and D) after short-term (4 week) and long-term (12 week) sucrose exposure in the intermittent-access two-bottle choice paradigm. Dopamine transporter (DAT) as determined by 125I-RTI-121 binding does not show any significant change short-term (4 week) and long-term (12 week) (E and F respectively). Each value represents the mean _ SEM of four animals per group. Significance of difference from vehicle-treated rats, ****p<0.0001, **p < 0.01, *p < 0.05.
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pone.0150270.g004: Long-term sucrose intake (12 weeks) increases α4(nonα6)β2* nAChR and decreases α6β2* nAChR levels in rat nucleus accumbens (NAc).Quantitative analyses of α4(nonα6)β2* nAChR binding using 125I-Epibatidine binding in the absence and presence of α-CtxMII show show a significant increase in α4(nonα6)β2* nAChRs (A and B) with a decrease in α6β2* nAChRs (C and D) after short-term (4 week) and long-term (12 week) sucrose exposure in the intermittent-access two-bottle choice paradigm. Dopamine transporter (DAT) as determined by 125I-RTI-121 binding does not show any significant change short-term (4 week) and long-term (12 week) (E and F respectively). Each value represents the mean _ SEM of four animals per group. Significance of difference from vehicle-treated rats, ****p<0.0001, **p < 0.01, *p < 0.05.

Mentions: The striatum contains two major nAChRs populations, the α4β2* and α6β2* subtypes [55]. To determine how long-term sucrose treatment modified α4β2* and α6β2* modulated subtype expression in the brain, we measured 125I-epibatidine binding in the absence and presence of α-CtxMII, which blocks α6β2* nAChRs (Fig 4A and 4B). Binding determined in the presence of α-CtxMII represents that occurring at α4β2* nAChRs, while the difference between total and α4β2* nAChR binding is defined as α6β2* nAChR binding. α4(non α6)β2* nAChRs were significantly increased in the NAc of both short-term and long-term sucrose-treated animals (unpaired T-test; p = 0.024 and <0.0001, respectively). By contrast, α6β2* nAChRs (Fig 4C and 4D) were significantly decreased short-term (unpaired t-test; p = 0.028) as well as long-term (unpaired t-test; p = 0.0035) with sucrose treatment. Lastly, we also compared the binding of the dopamine transporter (DAT) by 125I-RTI-121 binding to assess the modulation of dopamine shuttling in sucrose treated rats. There was no significant change observed short-term (4 week) and long-term (12 week) (unpaired T-test; p = 0.290 and 0.263, respectively).


Neuronal Nicotinic Acetylcholine Receptor Modulators Reduce Sugar Intake.

Shariff M, Quik M, Holgate J, Morgan M, Patkar OL, Tam V, Belmer A, Bartlett SE - PLoS ONE (2016)

Long-term sucrose intake (12 weeks) increases α4(nonα6)β2* nAChR and decreases α6β2* nAChR levels in rat nucleus accumbens (NAc).Quantitative analyses of α4(nonα6)β2* nAChR binding using 125I-Epibatidine binding in the absence and presence of α-CtxMII show show a significant increase in α4(nonα6)β2* nAChRs (A and B) with a decrease in α6β2* nAChRs (C and D) after short-term (4 week) and long-term (12 week) sucrose exposure in the intermittent-access two-bottle choice paradigm. Dopamine transporter (DAT) as determined by 125I-RTI-121 binding does not show any significant change short-term (4 week) and long-term (12 week) (E and F respectively). Each value represents the mean _ SEM of four animals per group. Significance of difference from vehicle-treated rats, ****p<0.0001, **p < 0.01, *p < 0.05.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4814119&req=5

pone.0150270.g004: Long-term sucrose intake (12 weeks) increases α4(nonα6)β2* nAChR and decreases α6β2* nAChR levels in rat nucleus accumbens (NAc).Quantitative analyses of α4(nonα6)β2* nAChR binding using 125I-Epibatidine binding in the absence and presence of α-CtxMII show show a significant increase in α4(nonα6)β2* nAChRs (A and B) with a decrease in α6β2* nAChRs (C and D) after short-term (4 week) and long-term (12 week) sucrose exposure in the intermittent-access two-bottle choice paradigm. Dopamine transporter (DAT) as determined by 125I-RTI-121 binding does not show any significant change short-term (4 week) and long-term (12 week) (E and F respectively). Each value represents the mean _ SEM of four animals per group. Significance of difference from vehicle-treated rats, ****p<0.0001, **p < 0.01, *p < 0.05.
Mentions: The striatum contains two major nAChRs populations, the α4β2* and α6β2* subtypes [55]. To determine how long-term sucrose treatment modified α4β2* and α6β2* modulated subtype expression in the brain, we measured 125I-epibatidine binding in the absence and presence of α-CtxMII, which blocks α6β2* nAChRs (Fig 4A and 4B). Binding determined in the presence of α-CtxMII represents that occurring at α4β2* nAChRs, while the difference between total and α4β2* nAChR binding is defined as α6β2* nAChR binding. α4(non α6)β2* nAChRs were significantly increased in the NAc of both short-term and long-term sucrose-treated animals (unpaired T-test; p = 0.024 and <0.0001, respectively). By contrast, α6β2* nAChRs (Fig 4C and 4D) were significantly decreased short-term (unpaired t-test; p = 0.028) as well as long-term (unpaired t-test; p = 0.0035) with sucrose treatment. Lastly, we also compared the binding of the dopamine transporter (DAT) by 125I-RTI-121 binding to assess the modulation of dopamine shuttling in sucrose treated rats. There was no significant change observed short-term (4 week) and long-term (12 week) (unpaired T-test; p = 0.290 and 0.263, respectively).

Bottom Line: We report that varenicline, an FDA-approved nicotinic acetylcholine receptor (nAChR) partial agonist that modulates dopamine in the mesolimbic reward pathway of the brain, significantly reduces sucrose consumption, especially in a long-term consumption paradigm.Furthermore, we show that long-term sucrose consumption increases α4β2 * and decreases α6β2* nAChRs in the nucleus accumbens, a key brain region associated with reward.Taken together, our results suggest that nAChR drugs such as varenicline may represent a novel treatment strategy for reducing sugar consumption.

View Article: PubMed Central - PubMed

Affiliation: Institute of Health and Biomedical Innovation, Queensland University of Technology at Translational Research Institute, Brisbane, Australia.

ABSTRACT
Excess sugar consumption has been shown to contribute directly to weight gain, thus contributing to the growing worldwide obesity epidemic. Interestingly, increased sugar consumption has been shown to repeatedly elevate dopamine levels in the nucleus accumbens (NAc), in the mesolimbic reward pathway of the brain similar to many drugs of abuse. We report that varenicline, an FDA-approved nicotinic acetylcholine receptor (nAChR) partial agonist that modulates dopamine in the mesolimbic reward pathway of the brain, significantly reduces sucrose consumption, especially in a long-term consumption paradigm. Similar results were observed with other nAChR drugs, namely mecamylamine and cytisine. Furthermore, we show that long-term sucrose consumption increases α4β2 * and decreases α6β2* nAChRs in the nucleus accumbens, a key brain region associated with reward. Taken together, our results suggest that nAChR drugs such as varenicline may represent a novel treatment strategy for reducing sugar consumption.

Show MeSH
Related in: MedlinePlus