Elisabet Jerlhag, PhDAssociate professor

Department of pharmacology

elisabet.jerlhag@pharm.gu.se

Sugar addiction- what is the preclinical and clinical

evidence to date

Sugar – sucrose/glucoseHigh fat

High fat/high sucrosePalatable foodBinge eating

The reward systems

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)

- 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

Addiction according DSM IV

Preclinical studies

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.

Sucrose is rewarding

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

Sucrose is rewarding

Sucrose increases accumbal dopamine release during each sugar binge

Rats are motivated to consume 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

Rats self-administer sucrose

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

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

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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..

Sucrose consumption escalates over time

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.

“Anxiety” – elevated plus maze “Depression” – forced swim test

Abstaining from sugars causes behavioural changes

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

Sucrose abstinence causes craving and relapse drinking

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.

Abstaining from sucrose increase intake at relapse

craving relapse

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..

Cross-sensitisation between sucrose and 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.

Rats maintained on an intermittent 12 h access sugar diet display and increased response to amphetamine

• 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)

Sucrose liking and alcohol

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?

Clinical studies

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)

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.

Foods with added amounts of fat and/or refined carbohydrates are associated with addictive-like food eating behaviours

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

Individuals with binge eating disorder prefer sucrose compared to healthy controls

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

Food stimuli when given with methylphenidate increase dopamine (caudate, putamen) in binge but not in non-binge eaters

Dopamine increases in the caudate were significantly correlated with the binge eating scores but not with BMI.

Binge eating and dopamine

Cassin SE, von Ranson KM. 2007 Is binge eating experienced as an addiction? Appetite 49(3):687-90

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%

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.

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

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

Obese individuals and rats have lower striatal D2R

Discussion

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

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?

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.

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?

Binge drinking affects endodegenous opiods in rats

Colantuoni, et al., 2002. Evidence that intermittent, excessive sugar intake causes endogenous opioid dependence. Obesity 10 (6), 478e488

Naloxon reduces sucrose induced withdrawal symptoms

Naloxon reduces general withdawal symptom

Naloxon reduces "anxiety” – elevated plus maze

The cholinergic-dopaminergic reward link

Reward seeking behaviors

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