Ad libitum administration of sucrose during adolescence causes changes in dopamine neurotransmission which are partially reversed by glucagon-like peptide

Ad libitum administration of sucrose during adolescence causes changes in dopamine neurotransmission which are partially reversed by glucagon-like peptide. Background: Overconsumption of sugar in children, associated with erratic eating behaviour, is linked to poor health and a higher risk to develop psychological problems [1]. It can cause abnormal fluctuation of metabolic hormones and the production of metabolites that can affect central neuronal activity. We asked the question whether prolonged continuous consumption of sucrose solution (5%) was sufficient to trigger alterations in dopaminergic neurotransmission and examined whether this could be modulated by glucagon-like peptide, a gut metabolic hormone which is known to interfere with food and drug rewarding systems [2].

Methods: Adolescent rats (PND 23-26) were administered sucrose 5% and water ad libitum, or water for 2 weeks, with or without the stable glucagon-like peptide agonist analogue exendin-4 (0.005 mg/kg/day, ip). After one week washout, rats were examined for their behavioural response to dopamine drugs and the electrophysiological characteristics of their ventral tegmental area (VTA) dopamine neurons, using single unit recording method under terminal anaesthesia. Statistical significance was ascertained by t-tests, or repeated measures ANOVA, as appropriate.

Results: Rats displayed a strong preference for sucrose that was not prevented by the administration of exendin-4. However, rats on sucrose treatment tend to consume slightly more food that the naïve/control rats and the exendin-4 treated animals. After 1 week washout, rats that were treated with sucrose-only displayed a stronger motor response than naïve rats to the administration of D-amphetamine (1 mg/kg), as shown by a larger increase in rearing activity (p<0.05, two-way ANOVA). Sucrose-treated rats also displayed a larger response than naïve animals to the D3 preferential agonist pramipexole (0.05 mg/kg, ip) on yawning and pica eating activities (p<0.01, two-way ANOVA). Interestingly, these behavioural changes were not observed in rats that were co-administered exendin-4 with sucrose. There were no significant changes in the electrophysiological characteristics of dopamine neurons (firing, burst and population activities) in sucrose treated and naïve/control animals. We then tested the effects of these chronic treatments on the ability of the preferential dopamine D3 receptor agonist pramipexole (cumulative doses 0.020-0.1 mg/kg, iv) to reduce the firing activity of VTA dopamine neurons (to test dopamine auto-receptor sensitivity). Animals treated with sucrose-only displayed a partial decrease in their responses to pramipexole (p<0.05, two-way ANOVA) which was more pronounced in VTA dopamine neurons from rats that were co-administered sucrose with exendin-4 (p<0.01, two-way ANOVA).

Conclusion: In conclusion, our data show that prolonged ad libitum access to sucrose to adolescent rats may alter brain circuits related to dopamine neurotransmission. It increases the behavioural effects of dopamine agonists, and is possibly associated with hypersensitivity of some postsynaptic dopamine receptors. These effects were partially prevented by exendin-4, which may elicit some protective effects on dopamine receptor function. On the other hand, we noticed that sucrose treatment induced a partial but significant decrease in the sensitivity of dopamine auto-receptors which was surprisingly exacerbated by exendin-4 co-administration, indicating that exendin-4 may exert differential effects on pre- and post-synaptic dopamine receptors. It will be of particular interest to find out how long these differential effects will persist.

References [1] M.D. Kendig Cognitive and behavioural effects of sugar consumption in rodents. A review Appetite, 80 (2014), pp. 41-54 [2] E. Jerlhag GLP-1 signaling and alcohol-mediated behaviors; preclinical and clinical evidence Neuropharmacology, 136 (2018), pp. 343-349