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Orexin and binge-like consumption: Sucrose, Saccharin, Ethanol

Orexin and binge-like consumption: Sucrose, Saccharin, Ethanol. ANDY DEEMER. Bingeing. Eating, Drinking, Drugs Orexin plays a role but… Caloric Status? (Non-)Caloric reward? Conditioning? Cue-induced reward seeking ♂ ♀ differences? Inconsistencies in several studies

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Orexin and binge-like consumption: Sucrose, Saccharin, Ethanol

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  1. Orexin and binge-like consumption:Sucrose, Saccharin, Ethanol ANDY DEEMER

  2. Bingeing • Eating, Drinking, Drugs • Orexin plays a role but… • Caloric Status? (Non-)Caloric reward? • Conditioning? Cue-induced reward seeking • ♂ ♀ differences? • Inconsistencies in several studies • Methodology related? Gender related? • Gender Differences • Orexin system • ♀ rat - higher Orexin A and OXR1 in HL than ♂ • Responses to food restriction • More studies = more differences revealed.

  3. Economic, Social and Therapeutic Potential of Orexin Research • Overconsumption of ______________ is a significant public health/economic issue. • Potential applications in obesity, diabetes, drug abuse • Understanding factors at play = better therapy • Caloric restriction important? • Gender diffs? • Bingeing substance (caloric/non, hedonic)

  4. Cason & Aston-Jones 2014 Role of orexin/hypocretin in conditioned sucrose-seeking in female rats • Orexin system sexual dimorphism • Eating disorders more common in women • OX system gender differences may play a role • Hedonic vs Homeostatic • Saccharin vs sucrose

  5. Cason & Aston-Jones 2014 Methods • Female Sprague-Dawley rats • Two Feeding Treatments • Ad libitum (AL) = free access • Food-restricted (FR) = • 1 daily feeding - maintained at 85% of AL body mass) • Drug = SB-334867 (OXR1 antagonist) • 3 doses used in this study 10, 20, and 30 mg/kg • Intraperitoneal (4 mL/kg) "SpragueDawleyRat" by Jean-Etienne Minh-Duy Poirrier - http://www.flickr.com/photos/jepoirrier/422469518/in/set-72157594329856603/. Licensed under CC BY-SA 2.0 via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:SpragueDawleyRat.jpg#/media/File:SpragueDawleyRat.jpg

  6. Cason & Aston-Jones 2014 Methods • Training – self-administer sucrose pellets • Press lever = get sucrose pellet • Compound cue (light and sound) • Fixed ratio (FR) 1 responding • Until 10 sessions earning > 9 sucrose pellets • Progressive ratio (PR) responding • Using mice previously trained from FR experiment • Find breakpoint for lever presses Images adapted from: http://rnpsychology.org/demo/index.htm

  7. Cason & Aston-Jones 2014 Fixed vs Progressive Ratio Schedule Progressive Ratio = 5ePelletNumber*0.2 – 5 Point at which no more rewards are earned over an hour = breakpoint.

  8. Cason & Aston-Jones 2014 Methods - Ratio Experiments • Fixed Ratio: • Train Vehicle/Drug injection Self-administration session • Progressive Ratio: • Use rats from fixed ratio experiment Train Injection • Self-administration session • Each rat was tested at multiple doses (2 doses) • Vehicle/Drug injected 30 minutes prior to • test sessions (all 3 of today’s papers)

  9. Cason & Aston-Jones 2014 Cue-induced reinstatement of sucrose-seeking • Take mice used for FR1 (but not PR) • Daily extinction sessions • Lever presses = nothing happens • Untraining • Until 2 consecutive sessions with < 25 active lever presses • Bring cues back (but no sucrose) • Measure SB effect on presses • 2 late extinction and 2 reinstatement sessions

  10. Cason & Aston-Jones 2014 Self-Admin Training # days to train similar for FR and AL rats Food-restricted More active and inactive presses + pellets earned

  11. Cason & Aston-Jones 2014 Fixed Ratio Experiment • FR more active presses + pellets earned • SD sig. effect on active presses only at high dose • No sig. effect of SD on pellets earned

  12. Cason & Aston-Jones 2014 Progressive Ratio Experiment • No effect of group or SB dose on breakpoint

  13. Cason & Aston-Jones 2014 Cue-induced reinstatement of sucrose-seeking • Food group effect • No sig. SB effect on CIRSS • Contrary to their previous findings in ♂ rats • AL and FR rats met extinction criteria < 5 extinction sessions • SB attenuation of active presses - late extinction

  14. Cason & Aston-Jones 2014 Cason & Aston-Jones Take Homes • Cue-induced reinstatement and SB-334867 • Sex-dependent story • ♀ - OXR1 unnecessary; important in ♂ • Increased extinction responding • Orexinrole in learning/reward valuation in females? • Future Research: • Systems at play in ♀ cue-induced seeking (e.g. leptin, insulin, ghrelin, estrogen) • Untangling ♂♀ circuitry differences • SB-334867 effects on Fos expression in orexin targets

  15. Cason & Aston-Jones 2014 Cason & Aston-Jones Take Homes • Agree with conclusion? • “Our findings show that OxR1 regulates operant responding for sucrose reinforcement, but not motivation to work…” • Fig 4, Panel 1: • With OXR1 unblocked, try less = regulates motivation to work?

  16. Alcaraz-Iborra et al. 2014 Binge-like consumption of caloric and non-caloric palatable substances in ad libitum-fed C57BL/6J mice: Pharmacological and molecular evidence of orexin involvement • Objectives: • SB-334867 effect on binge consumption of sucrose and saccharin in ad libitum-fed mice • Effect of repetitive sucrose and saccharin bingeing on OX mRNA expr in LH • Mirror chronic morphine, cocaine, ethanol?

  17. Alcaraz-Iborra et al. 2014 Methods • Male C57BL/6J (8 wks old @ start) • Drug = SB-334867 (OXR1 antagonist) • Intraperitoneal (10 mL/kg) • Drinking-in-the-Dark (DID) procedure • High voluntary bingeing on ethanol, sucrose, saccharin during early part of dark cycle • Provide sucrose/saccharin ~ 3 hrs. into dark cycle • Open-field activity monitoring • qPCR

  18. Alcaraz-Iborra et al. 2014 Experiment 1: Effect of SB on sucrose and saccharin binge drinking • Binge-training / screening • 3 days of DID (2 hrs bottle access) • ip injection w/ vehicle - habituation • 4th day = test day (4 hrs bottle access) • Injection of SB (10, 20 or 30 mg/kg) or vehicle 30 min prior to test • Measure: • Liquid imbibed • Calories consumed (chow included)

  19. Alcaraz-Iborra et al. 2014 • ip SB-334867 ↓ sucrose and saccharin bingeing • Higher doses ↓ sucrose bingeing more than lowest dose • Strange calories consumed data in saccharin group *

  20. Alcaraz-Iborra et al. 2014 Experiment 2: Effect of SB on locomotor activity • Open-field locomotor activity monitoring • Days 1-3: Habituate to injection (vehicle) and activity chamber & record behavior • Day 4: 30 mg/kg SB → activity chamber • Evaluate difference • Purpose: SB-334867 impact distance traveled and movement time? • Explanation for reduced fluid/food intake? • Results: No sig. diff. • The means they present seem fairly different, but no sig. diff

  21. Alcaraz-Iborra et al. 2014 Experiment 3: Repeated sucrose/saccharin bingeing and mRNA expression in the HL • Repeated bingeing (DID – i.e. voluntary) • Four 2-hour daily binge sessions • Sucrose, Saccharin, or Water group • Brain dissection → LH removed → RNA extracted • qPCR with GAPDH for comparison

  22. Alcaraz-Iborra et al. 2014 • Repeated bingeing ↓ HL OX mRNA • Sucrose group: 5x > water intake

  23. Alcaraz-Iborra et al. 2014: Take-homes • OXR1 role in caloric bingeing in AL-fed animals • SB-334867 ↓ caloric & non-caloric bingeing in AL-fed ♂ mice • Unclear why in AL-fed mice (ip injection) • Future Research: Site-directed SB studies • 1st evidence of OXR1 role in non-caloric bingeing/hedonic overconsumption • Repeated daily bingeing ↓ HL OX expr (qPCR)

  24. Alcaraz-Iborra et al. 2014: Take-homes • SB effect on bingeing not caused by SB-altered locomotion. • Why not show more data? • DID potential issue: • Energy status at time of DID • Future Research: Alter energy status during DID

  25. Olney et al. 2015 Binge-like consumption of Ethanol and Other Salient Reinforcers is Blocked by Orexin-1 Receptor Inhibition and Leads to a Reduction in Hypothalamic Orexin Immunoreactivity Illustration by Emily Coren.

  26. Olney et al. 2015 Purpose • Characterize OXR1 role in “binge” drinking • Ethanol, sucrose, saccharin • Binge-like EtOH and Sucrose drinking • Effect on OX immunoreactivity in HL • Effect of ip SB • SB specificity for EtOH modulation • Compare with saccharin bingeing

  27. Olney et al. 2015 Methods • C57BL/6J male mice (7-9 wks old) • SB-334867 (0, 5, 10 mg/kg) • Bingeing cycles: • 1 or 3 cycles; EtOH or Sucrose • DID (modified 2 hrs not 4 – short drug action) • Except experiment 1 – used 4 hrs. • Blood alcohol content • Brain dissection • Orexin A immunoreacitivy (LH and PFA)

  28. Olney et al. 2015 Methods • SB ip injection • Reduced EtOH consumption? Saccharin? • Each mouse, all doses • 4 day cycle with 3 days rest between doses • Locomotion • Open field test with Saccharin group mice • 2 hours • 0 or 10 mg/kg SB

  29. Olney et al. 2015 • No cycle effect on: • EtOHConsump. • Sucrose Consump • BEC • EtOH bingeing ↓ LH OX levels

  30. Olney et al. 2015 EtOH Bingeing reduced HL OX

  31. Olney et al. 2015 • SB ↓ EtOH consumption • Short-lived (Hr 1 vs. Hr 2) • BEC levels parallel total consumption • SB ↓ Saccharin consumption • Only signif. largest dose over 2 hrs. • Take Home: SB effect on ↓ bingeing not specific to EtOH or caloric foods

  32. Olney et al. 2015 Locomotion • Like Alcaraz-Iborra: • SB-induced general lethary cause of reduced bingeing? • Open field test: • No impairment of locomoter activity

  33. Olney et al. 2015: Take-homes • OXR1 role in caloric and non-caloric bingeing • Not EtOH specific • Bingeing ↓ HL OXR1 • SB effects not due to altered locomotion • DID 4hr vs 2hr • Duration of drug effect may be less than 4 hrs • Inconsistent dose effects between researchers • SB variability: Supplier effects, batch effects • Future Research: • Mechanisms responsible for post-binge OX and OXR1 levels • Interplay of dynorphin and OX w/in VTA

  34. Overall Take-homes • Site-specific studies necessary (not ip injection) • - ID OX circuits underlying phenomena • - VTA likely involved

  35. Thank You!

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