Transcript PowerPoint-presentation

Sugar addiction
- what is the preclinical and clinical
evidence to date
Elisabet Jerlhag, PhD
Associate professor
Department of pharmacology
[email protected]
Sugar – sucrose/glucose
High fat
High fat/high sucrose
Palatable food
Binge eating
The reward systems
LDTg
nAChR
VTA
ACh
NAc
DA
NTS
-
Role of the reward system
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Mediate the rewarding properties of natural rewards as well as
addictive drugs (dopamine release in reward areas including
nucleus accumbens (NAc-ventral striatum))
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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)
Addiction according DSM IV
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Tolerance – increased intake over time
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Use larger amounts, over a longer period than was intended (loss
of control) – increased intake over time
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Withdrawal symptoms– defined behavioural responses in relation
to abstinence
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Persistent desire or unsuccessful efforts to cut down or control
use (craving  relapse) – abstinence causes relapse with
increased intake. Motivation to obtain drug.
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A great deal of time is spent in activities necessary to obtain drug,
use drug, or recover from its effects
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Important social, occupational, or recreational activities are given
up or reduced because of drug use
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The use is continued despite knowledge of having a persistent or
recurrent physical or psychological problem
Preclinical studies
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.
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
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
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
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Sucr Chow
Sucr Chow
Sucr Chow
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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
Sucr Chow
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..
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.
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
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.
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
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.
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)
Addiction according DSM IV
-
Tolerance – increased intake over time
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Use larger amounts, over a longer period than was intended (loss
of control) – increased intake over time
However, these effects are only seen
- Withdrawal symptoms– defined behavioural responses in relation
if rats
are bingeing sucrose. Is it
to abstinence
behavior
rather
thanefforts
sucrose.
- Persistent desire
or unsuccessful
to cut down orEating
control
use (craving  relapse) – abstinence causes relapse with
addiction?
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
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)
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.
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
Binge eating and dopamine
Binge eaters
Non binge eaters
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.
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
Binge eating – YFAS
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Tolerance – 49.4%
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Use larger amounts, over a longer period than was intended
92.4%
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Withdrawal symptoms – 67.1%
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Persistent desire or unsuccessful efforts to cut down or control
use - 83.5%
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A great deal of time is spent in activities necessary to obtain
drug, use drug, or recover from its effects – 59.5%
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Important social, occupational, or recreational activities are
given up or reduced because of drug use – 48.1%
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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
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.
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
Discussion
Sucrose compared to cocaine
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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
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
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Relevance of preclinical animal studies?
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Sugar, fat, sugar/fat, palatable, or food intake behaviour?
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Is sucrose more rewarding than cocaine?
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Food addiction - eating addiction – binge eating – compulsive
overeating
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Comorbidities between binge eating and alcohol dependence
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How?? In what way can a behaviour cause reward and change the
reward systems? Via appetite hormones?
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Terminology between different fields
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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
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
The cholinergic-dopaminergic reward link
LDTg
nAChR
VTA
ACh
NAc
DA
NTS
Reward seeking
behaviors