Neuronal Nicotinic Acetylcholine Receptor Modulators Reduce Sugar Intake

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.

Fig 1. Long-term exposure to sucrose (12 weeks) in rats using the intermittent-access two-bottle choice paradigm increased the efficacy of varenicline.

Varenicline (2 mg/kg) significantly decreased sucrose consumption (Fig 1A) after short-term (4 weeks) exposure to sucrose. Whereas, both (1 and 2 mg/kg of varenicline significantly decreased sucrose consumption (Fig 1B) following long-term (12 weeks) sucrose exposure. Varenicline (2 mg/kg) significantly decreased saccharin consumption (Fig 1C) after short-term (4 weeks) exposure to saccharin. The values are expressed as mean sucrose intake (g/kg) ± SEM (repeated-measures ANOVA followed by Newman—Keuls post hoc test). *, P < 0.05; **, P < 0.01 compared with vehicle, n = 10–12.

Fig 2. Mecamylamine significantly decreased sucrose intake in rats consuming sucrose short-term (4 weeks) and long-term (12 weeks) using the intermittent-access two-bottle choice paradigm.

Mecamylamine (2 mg/kg) significantly decreased sucrose consumption in short-term (4 weeks) and long-term (12 weeks) sucrose exposure rats (Fig 2A and 2B). The values are expressed as mean sucrose consumed (g/kg) ± SEM (repeated-measures ANOVA followed by Newman—Keuls post hoc test). *, P < 0.05; **, P < 0.01; ***, P < 0.001 compared with vehicle, n = 12.

Fig 3. Cytisine significantly decreased sucrose intake in rats consuming sucrose short-term (4 weeks) and long-term (12 weeks) using the intermittent-access two-bottle choice paradigm.

Cytisine (4 mg/kg) significantly decreased sucrose consumption (Fig 3A and 3B) after the onset of drinking in short-term (4 weeks) and long-term (12 weeks) sucrose exposure rats. The values are expressed as mean sucrose consumed (g/kg) ± SEM (repeated-measures ANOVA followed by Newman—Keuls post hoc test). *, P < 0.05; **, P < 0.01; ***, P < 0.001 compared with vehicle, n = 12.

Fig 4. 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.