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Sugar addiction - what is the preclinical and clinical evidence to date

Sugar addiction - what is the preclinical and clinical evidence to date. Elisabet Jerlhag , PhD Associate professor Department of pharmacology elisabet.jerlhag@ pharm.gu.se. Sugar – sucrose/glucose High fat High fat/high sucrose Palatable food Binge eating. The reward systems.

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Sugar addiction - what is the preclinical and clinical evidence to date

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  1. Sugar addiction- what is the preclinical and clinical evidence to date • Elisabet Jerlhag, PhDAssociate professorDepartment of pharmacology • elisabet.jerlhag@pharm.gu.se

  2. Sugar – sucrose/glucose High fat High fat/high sucrose Palatable food Binge eating

  3. The reward systems

  4. Role of the reward system • Mediate the rewarding properties of natural rewards as well as addictive drugs (dopamine release in reward areas including nucleus accumbens (NAc-ventral striatum)) • Enhance the incentive salience of motivated behaviours such as food seeking (self-administration models) • Individuals with an addiction appear to have a dysbalance/dysfunction in the reward systems (i.e reduced numbers of dopamine receptors in ventral striatum)

  5. Addiction according DSM IV • Tolerance – increased intake over time • Use larger amounts, over a longer period than was intended (loss of control) – increased intake over time • Withdrawal symptoms– defined behavioural responses in relation to abstinence • Persistent desire or unsuccessful efforts to cut down or control use (craving  relapse) – abstinence causes relapse with increased intake. Motivation to obtain drug. • A great deal of time is spent in activities necessary to obtain drug, use drug, or recover from its effects • Important social, occupational, or recreational activities are given up or reduced because of drug use • The use is continued despite knowledge of having a persistent or recurrent physical or psychological problem

  6. Preclinical studies

  7. Sucrose is rewarding Sucrose dose-dependently increases accumbal dopamine release when rats consume sucrose for the first time Hajnal, Smith, Norgren, 2004. Oral sucrose stimulation increases accumbens dopamine in the rat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 286, R31eR37.

  8. Sucrose is rewarding Sucrose increases accumbal dopamine release during each sugar binge Rada, Avena, Hoebel 2005 Daily bingeing on sugar repeatedly releases dopamine in the accumbens shell. Neuroscience 134, 737e744. Avena, Rada Moise, Hoebel 2006 Sucrose sham feeding on a binge schedule releases accumbens dopamine repeatedly and eliminates the acetylcholine satiety response. Neuroscience. 139:813–820

  9. Rats are motivated to consume sucrose Rats self-administer sucrose Alsiö, Pickering, Roman, Hulting, Lindblom, Schiöth (2009) Motivation for sucrose in sated rats is predicted by low anxiety-like behavior. Neurosci Lett. 1;454(3):193-7

  10. Sucrose changes the reward systems Binge drinking rats have a higher number of DA1 receptors and a lower number of DA2 receptors in reward areas Sucr Chow Sucr Chow Sucr Chow Sucr Chow Sucr Chow Sucr Chow * * * * Colantuoni C, Schwenker J, McCarthy J, Rada P, Ladenheim B, Cadet JL, Schwartz GJ, Moran TH, Hoebel BG. (2001) Excessive sugar intake alters binding to dopamine and mu-opioid receptors in the brain. Neuroreport.12:3549–3552

  11. Sucrose consumption escalates over time Rada P, Avena NM, Hoebel BG 2005. Daily bingeing on sugar repeatedly releases dopamine in the accumbens shell. Neuroscience 134, 737e744. Wideman, et al., 2005. Implications of an animal model of sugar addiction, withdrawal and relapse for human health. Nutri. Neurosci. 8 (5e6), 269e276. Avena, 2007. Examining the addictive-like properties of binge eating using an animal model of sugar dependence. Exp. Clin. Psychopharmacol. 15 (5), 481e491..

  12. Abstaining from sugars causes behavioural changes “Anxiety” – elevated plus maze “Depression” – forced swim test Avena NM, Rada P, Hoebel BG (2008) Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake. Neurosci Biobehav Rev. 32(1):20-39.

  13. Sucrose abstinence causes craving and relapse drinking Cue increases the motivation to lever press for sucrose following abstinence Counotte DS1, Schiefer C, Shaham Y, O'Donnell P. (2014) Time-dependent decreases in nucleus accumbens AMPA/NMDA ratio and incubation of sucrose craving in adolescent and adult rats. Psychopharmacology (Berl) 231(8):1675-84

  14. Abstaining from sucrose increase intake at relapse craving  relapse Avena NM, Long KA, Hoebel BG. 2005 Sugar-dependent rats show enhanced responding for sugar after abstinence: evidence of a sugar deprivation effect. Physiol Behav, 84(3):359-62.

  15. Photostimulation of the LH-VTA Pathway Promotes Sucrose Seeking in the Face of a Negative Consequence Nieh, Matthews, Allsop, Presbrey, Leppla, Wichmann, Neve, Wildes, Tye (2015) Decoding neural circuits that control compulsive sucrose seeking Cell. 2015 Jan 29;160(3):528-41. doi: 10.1016/j.cell.2015.01.003. .

  16. Cross-sensitisation between sucrose and amphetamine Rats maintained on an intermittent 12 h access sugar diet display and increased response to amphetamine N. M. Avena, B. G. Hoebel, A diet promoting sugar dependency causes behavioral cross-sensitization to a low dose of amphetamine. Neuroscience 122, 17-20 (2003). AND FOR COCAINE - Collins GT, Chen Y, Tschumi C, Rush EL, Mensah A, Koek W, France CP 2015 Effects of consuming a diet high in fat and/or sugar on the locomotor effects of acute and repeated cocaine in male and female C57BL/6J mice. Exp Clin Psychopharmacol. 23(4):228-37.

  17. Sucrose liking and alcohol • Alcohol-preferring rats as well as alcohol dependent humans prefer higher concentrated sweet solutions compared to alcohol-avoiding rats/controls (Sinclair et al 1992; Kampov-Polevoy al al 2001) • Humans with a sweet liking phenotype (preference for stronger sweet taste) is closely linked to genetic risk for alcoholism (Kampov-Polevoy al al 2001;Pepino and Mennella, 2007; Wronski et al., 2007)

  18. Addiction according DSM IV • Tolerance – increased intake over time • Use larger amounts, over a longer period than was intended (loss of control) – increased intake over time • Withdrawal symptoms– defined behavioural responses in relation to abstinence • Persistent desire or unsuccessful efforts to cut down or control use (craving  relapse) – abstinence causes relapse with increased intake. Motivation to obtain drug. • A great deal of time is spent in activities necessary to obtain drug, use drug, or recover from its effects • Important social, occupational, or recreational activities are given up or reduced because of drug use • The use is continued despite knowledge of having a persistent or recurrent physical or psychological problem However, these effects are only seen if rats are bingeing sucrose. Is it behavior rather than sucrose. Eating addiction?

  19. Clinical studies

  20. Genetic alterations and sucrose intake in humans • Haplotypes in the ghrelin receptor gene (AGACGT and GACGT) is associated with increased sucrose intake (by 10%) in healthy individuals (Landgren et al 2011) • A genetic variant (G/G variant of A118G) of the my opiod receptor (OPRM1) is associated with higher preference for sweet and fatty food (Davis et al 2011)

  21. Foods with added amounts of fat and/or refined carbohydrates are associated with addictive-like food eating behaviours Schulte EM, Avena NM, Gearhardt AN. 2015 Which foods may be addictive? The roles of processing, fat content, and glycemic load.PLoS One. 10(2):e0117959.

  22. Individuals with binge eating disorder prefer sucrose compared to healthy controls Dalton M1, Blundell J, Finlayson G. (2013) Effect of BMI and binge eating on food reward and energy intake: further evidence for a binge eating subtype of obesity. Obes Facts. 2013;6(4):348-59

  23. Binge eating and dopamine Binge eaters Non binge eaters Dopamine increases in the caudate were significantly correlated with the binge eating scores but not with BMI. Food stimuli when given with methylphenidate increase dopamine (caudate, putamen) in binge but not in non-binge eaters Wang GJ, Geliebter A, Volkow ND, Telang FW, Logan J, Jayne MC, Galanti K, Selig PA, Han H, Zhu W, Wong CT, Fowler JS. 2011 Enhanced striatal dopamine release during food stimulation in binge eating disorder. Obesity (Silver Spring). 19(8):1601-8

  24. Binge eating – YFAS • Tolerance – 49.4% • Use larger amounts, over a longer period than was intended 92.4% • Withdrawal symptoms – 67.1% • Persistent desire or unsuccessful efforts to cut down or control use - 83.5% • A great deal of time is spent in activities necessary to obtain drug, use drug, or recover from its effects – 59.5% • Important social, occupational, or recreational activities are given up or reduced because of drug use – 48.1% • The use is continued despite knowledge of physical or psychological problem – 91.1% Cassin SE, von Ranson KM. 2007 Is binge eating experienced as an addiction? Appetite 49(3):687-90

  25. The time for glucose to activate dopamine releases is longer in patients with Prader-Willi syndrome (characterized by e.g. bingeing of foods ) compare to healthy controls Shapira NA1, Lessig MC, He AG, James GA, Driscoll DJ, Liu Y (2005) Satiety dysfunction in Prader-Willi syndrome demonstrated by fMRI. J Neurol Neurosurg Psychiatry. 76(2):260-2.

  26. Obese individuals and rats have lower striatal D2R Michaelides M, Thanos PK, Volkow ND, Wang GJ. 2012 Dopamine-related frontostriatal abnormalities in obesity and binge-eating disorder: emerging evidence for developmental psychopathology. Int Rev Psychiatry. 24(3):211-8

  27. Discussion

  28. Sucrose compared to cocaine • What do the rats prefer? • How much are the willing to work for sucrose/cocaine? • How much punishment is sucros/cocaine worth? • What is the maximal motivation for obtaining sucrose/cocaine? Sugar addiction: pushing the drug-sugar analogy to the limit. Ahmed, Serge; Guillem, Karine; Vandaele, Youna Current Opinion in Clinical Nutrition & Metabolic Care. 16(4):434-439

  29. Rats prefer sucrose over cocaine Lenoir M1, Serre F, Cantin L, Ahmed SH. 2007 Intense sweetness surpasses cocaine reward. PLoS One. 2007 Aug 1;2(8):e698.

  30. Discussion • Relevance of preclinical animal studies? • Sugar, fat, sugar/fat, palatable, or food intake behaviour? • Is sucrose more rewarding than cocaine? • Food addiction - eating addiction – binge eating – compulsive overeating • Comorbidities between binge eating and alcohol dependence • How?? In what way can a behaviour cause reward and change the reward systems? Via appetite hormones? • Terminology between different fields • How should sugar addiction/ eating addiction be studied in humans? Which feature is most important? Does this differ between disciplines?

  31. Binge drinking affects endodegenous opiods in rats

  32. Naloxon reduces sucrose induced withdrawal symptoms Naloxon reduces general withdawal symptom Naloxon reduces "anxiety” – elevated plus maze Colantuoni, et al., 2002. Evidence that intermittent, excessive sugar intake causes endogenous opioid dependence. Obesity 10 (6), 478e488

  33. The cholinergic-dopaminergic reward link LDTg VTA nAChR ACh NAc DA NTS - Reward seeking behaviors

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