Guest Post: Characterising high fructose corn syrup self-administration in laboratory rats

It’s January, and across the country millions of people have promised themselves that they will eat less, loose weight and become healthier. But why do some people eat more than others? No matter what they try there seems to be no way to stop their overeating. Public education is a powerful tool to combat some of these issues but what happens when it turns into an addiction? It is challenging to provide accurate information when food addiction is a little studied field. In an effort to answer these questions scientists can use laboratory rodents to explore neurobiological mechanisms involved in relapse to drug-seeking behavior, comorbid mood and substance dependence disorders, as well as perseverative reward seeking. These complex answers cannot be solely obtained though human patients because the physiological and psychological mechanisms that influence food addiction are not fully understood.

AnneMare Levy is a PhD student and Francesco Leri is an Associate Professor of Neuroscience and Applied Cognitive Science in the Department of Psychology at the University of Guelph. In the article below these scientists explain how and why the development of a new animal model to understand the addictive properties of some foods is necessary and how its use can begin to answer some of these questions. They believe that through studying rats their findings could lead to novel pharmacological interventions for obese individuals that could help them selectively reduce intake of unhealthy foods.

The views expressed below are that of the authors alone and do not necessarily reflect the views of her employer or institution.

Overconsumption of foods high in sugars and saturated fats is an important contributing factor to the modern epidemic of overweight and obesity1, which are leading causes of metabolic disorders and cardiovascular diseases2. It is therefore important to understand why patterns of excessive food intake develop and persist despite the negative health consequences. Considerable evidence supports the hypothesis that, for some people, addiction to food may motivate these behaviours3-4. In fact, behavioural and neurobiological similarities between obesity and drug dependence support the “food addiction” hypothesis5-8 and studies in both humans and laboratory animals have identified a variety of biological and behavioural indicators of “food addiction”9-12.

The food addiction hypothesis suggests that similar to drugs of abuse, particular foods should reinforce behaviours that lead to their consumption. Therefore, to assess the addictive potential of such foods, we adapted procedures commonly used for studying the reinforcing properties of drugs of abuse (i.e. operant intravenous drug self-administration) to the investigation of operant self-administration of sweet solutions delivered directly into the mouth of rats. To this end, an intraoral cannula was surgically implanted13 into the cheek of rats and the animals were subsequently trained to press a lever to voluntarily receive a test solution directly into their mouth; hence the term intraoral self-administration. The sweet solution selected for testing was high fructose corn syrup (HFCS) because, although controversial14, there is evidence that HFCS may be linked to the modern epidemic of obesity15.

corn-syrup

The disadvantage of requiring minor surgery to employ this procedure is offset by several advantages that make intraoral self-administration in rats optimal for studying the reinforcing properties of sweet solutions. First, an operant response (i.e., pressing a lever) is required to obtain an infusion and therefore it is possible to modify the schedule regulating the relationship between response requirement and delivery of intraoral infusions. Hence, by employing a progressive ratio (PR) schedule16, whereby more lever presses are required to get more sweet solution, it is possible to assess how much an animal “wants”17 the next infusion and by employing a continuous schedule of reinforcement, whereby each lever response is reinforced, it is possible to measure total intake, escalation of intake, and the development of bingeing behaviour.  Second, intraoral self-administration allows testing of any concentration and any volume of any water-soluble food additive. The importance of controlling and manipulating concentration/volume ratios is mandatory in experiments where intake can be modulated both by the caloric value of a solution (i.e., nutrient-specific satiety) and by how much of that solution can be consumed within a given period of time (i.e., fullness)18. Third, intraoral self-administration shortens the delay between the operant response and the delivery of the primary reinforcer, a factor that plays an important role in the acquisition and maintenance of operant behaviour19-21. Finally, this procedure allows for the delivery of passive intraoral infusions of controlled quantities of the test solution.  This makes it possible to measure orofacial responses of “liking” (objective hedonic reaction such as tongue protrusions)22 as well as administer priming infusions23 of the test solution prior to tests of reinstatement of sweet-seeking behaviour.

The objective of this study was to characterize HFCS self-administration behaviour in laboratory rats. It was important to establish a reliable animal model of self-administration because it will allow future studies to identify and manipulate the neurobiological substrates that are responsible for the escalation and maintenance of excessive food intake. Moreover, using this animal model, the rats will be able to self-administer solutions for extended periods of time (i.e. months) to establish how sweeteners, such as HFCS, may contribute to the development of metabolic disorders.  For all experiments, rats were surgically implanted with an intraoral cannula while under an anaesthetic. Post-operative care included administering analgesic, daily flushing of the cannula with an anti-bacterial solution as well as closely monitoring weight gain and food intake. Following recovery, rats received one 3-hour self administration session per day, whereby, rats were placed into a standard operant chamber and trained to lever press to receive intraoral infusions of different concentrations of HFCS (8%, 25%, and 50%) on either continuous or PR schedules of reinforcement, as previously described.

It was found that the behavioural profile of rats responding for HFCS is similar to the pattern of intake observed when rats self-administer drugs of abuse24-25. Using intraoral self-administration, it was established that on a continuous schedule of reinforcement, rats acquire and maintain intraoral self-administration of a wide range of HFCS concentrations (8%, 25% or 50%), and that rats adjust their self-administration behaviour according to the different concentrations (i.e., rats self-administer twice as much a 25% solution than a 50% solution)13.  Furthermore, higher concentrations of HFCS engender higher responding on the PR schedule of reinforcement, suggesting that increasing the HFCS content likewise increases the reinforcing value of the solution. The relationship between operant responding and HFCS concentration on continuous and progressive ratio schedules is similar to the dose-response relationships observed when rats self-administer drugs of abuse24.

It was further noted that total intake of 25% HFCS escalated over three weeks of testing, possibly reflecting the development of “bingeing” behaviour9,13. In fact, after a week of self-administration, rats displayed a clear period of elevated intake during the initial 90 minutes of each self-administration session and this “loading” increased in magnitude over the weeks of training. This effect is reminiscent of escalation of drug intake and increased loading that are observed when rats have prolonged and/or repeated access to drugs of abuse26.

The results of these experiments also indicated that HFCS is reinforcing because of its caloric content. Even though 0.1% saccharin (a non-caloric sweetener)27 and 25% HFCS produce similar hedonic reactions (i.e. the perceived palatability of the two solutions is similar in tests of taste reactivity17), 0.1% saccharin could not maintain self-administration at the same level that 25% HFCS. Moreover, when substituted for HFCS, a wide range of saccharin concentrations (0.01%, 1.0%, and 10%) significantly reduced self-administration behaviour, indicating that HFCS reinforcement is largely determined by its caloric content rather than its palatability.

Taken together, these experiments indicate that intraoral infusion of HFCS reinforces lever-pressing in rats, and this behaviour was maintained primarily by the caloric content and not the palatability of the solution made available for self-administration.  In these rats, stable self-administration was maintained for up to three weeks, it was concentration-dependent, and rats developed a tendency to “binge” on HFCS at the start of sessions. Using intraoral self-administration, future studies should investigate the possibility that HFCS engenders other “addictive-like” behaviors, and whether escalation of HFCS self-administration can be causally linked to the development of metabolic changes (i.e., weight gain, insulin resistance) associated with obesity and type-2 diabetes.

AnneMarie Levy & Francesco Leri

University of Guelph

University of Guelph

Department of Psychology, NACS

References

1. Barry D, Clarke M, Petry NM (2009) Obesity and Its Relationship to Addictions: Is Overeating a Form of Addictive Behavior? Am J Addict 18: 439-451.

2. World Health Organization (2013) Obesity and overweight Fact sheet N°311. Available: http://www.who.int/mediacentre/factsheets/fs311/en/index.html#. Accessed 20 June 2013.

3. Davis C, Carter JC (2009) Compulsive overeating as an addiction disorder: a review of theory and evidence. Appetite 53: 1-8.

4. Ifland JR, Preuss HG, Marcus MT, Rourke KM, Taylor WC, Burau K, Jacobs WS, Kadish W, Manso G (2009) Refined food addiction: a classic substance use disorder. Med Hypotheses 72: 518-526.

5. Avena NM, Bocarsly ME, Hoebel BG, Gold MS (2011) Overlaps in the nosology of substance abuse and overeating: the translational implications of “food addiction”. Curr Drug Abuse Rev 4: 133-139.

6. Volkow N, Wise RA (2005) How can drug addiction help us understand obesity? Nat Neurosci 8: 555-560.

7. Fortuna J (2012) The Obesity Epidemic and Food Addiction: Clinical Similarities to Drug Dependence. J Psychoactive Drugs 44: 56.

8. Levy AM, Salamon A, Tucci M, Limebeer CL, Parker LA, Leri F (2012) Co-sensitivity to the incentive properties of palatable food and cocaine in rats; implications for co-morbid addictions. Addict Biol:  doi: 10.1111/j.1369-1600.2011.00433.

9. Avena NM, Rada P, Hoebel BG (2008) Evidence for sugar addiction: behavioural and neurochemical effects of intermittent, excessive sugar intake. Neurosci Biobehav Rev 32, 20-39.

10. Gearhardt AN, Davis C, Kuschner R, Brownell KD (2011) The addiction potential of hyperpalatable foods. Curr Drug Abuse Rev 4: 140-145.

12. Johnson PM, Kenny PJ (2010) Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats. Nat Neurosci 13:  635-644.

13. Levy AM, Limebeer CL, Ferdinand J, Shillingford U, Parker LA, et al. (2014) A novel procedure for evaluating the reinforcing properties of tastants in laboratory rats: operant intraoral self-administration. JoVE: in press.

14. White JS (2008) Straight talk about high-fructose corn syrup: what it is and what it ain’t. Am J Clin Nutr. 88: 1716S-1721S.

15. Bray GA, Nielsen SJ, Popkin BM (2004) Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity, Am J Clin Nutr 79: 537-543.

16. Richardson NR, Roberts DC (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66: 1-11.

17. Berridge, K. C., & Robinson, T. E., Parsing reward. Trends in Neuroscience 26 (11), 507-501(2003).

18. Houpt, K. A. Gastrointestinal factors in hunger and satiety. Neuroscience and Biobehavioural Reviews 6 (2), 145-164 (1982).

19. Panksepp, J. & Trowill, J. A. Intraoral self injection: I. Effects of delay of reinforcement on resistance to extinction and implications for self-stimulation. Psychonomic Sciences 9 (7), 405-406 (1967)

20. Mazur, J. E. Effects of rate of reinforcement and rate of change on choice behaviour in transition. Journal of Experimental Psychology 50 (2), 111-128 (1997).

21. Samaha, A. N., & Robinson, T. E. Why does the rapid delivery of drugs to the brain promote addiction? Trends in Pharmacological Sciences 26 (2), 82-87 (2005).

22. Berridge, K. C., & Kringelbach, M. L. Affective neuroscience of pleasure: reward in humans and animals. Psychopharmacology (Berl) 199 (3), 457-480 (2008)

23. Shaham, Y., Shalev, U., Lu, L., De Wit, H., & Stewart, J. The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology (Berl) 168 (1-2), 3-20 (2003).

24. Deroche-Gamonet V, Belin B, Piazza PV (2004) Evidence for addiction-like behaviour in the rat. Science 305: 1014-1017.

25. Carroll ME, Lac ST (1997) Acquisition of IV amphetamine and cocaine self-administration in rats as a function of dose.  Psychopharmacology 129: 206-214.

26. Ahmed SH, Koob GF (1998) Transition from moderate to excessive drug intake: change in hedonic set point. Science 282: 298-300.

27. Miller SA, Frattali VP (1989) Saccharin. Diabetes Care 12: 74-80.

One response to “Guest Post: Characterising high fructose corn syrup self-administration in laboratory rats

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