I have been studying the neurobehavioral aspects of food and drug reinforcement for the past 5 years (read more about it on my profile page). This involves using rats to mimic basic human behaviors surrounding food and drug intake. I then manipulate various neurotransmitter systems by using drugs and observe the effects this manipulation has on the behaviors I am interested in.
What’s important to this type of research is that we constantly challenge and evaluate the validity of using these animal models to study complex human diseases and disorders. Validity can be divided into several categories, but I’m going to focus on two in particular and relate them to an animal model of binge food intake. These two types of validity are predictive validity and construct validity:
- Predictive validity, when comparing animal research to human research, refers to the ability for some measure of animal behavior to predict a human behavior.
- Construct validity in the case of comparing animal studies to human studies is the degree to which the animal behavior accurately reflects a human construct.
Predictive validity and construct validity are important for preclinical studies (that’s before humans get involved) because they aid in determining what we can reasonably infer or conclude from data. Sometimes both are present, sometimes one, and sometimes none at all (the last one is obviously not very useful).
Here’s where I need YOUR feedback: I’m interested in discussing the validity of a study by Cifani et al. (2009).
In this work, the researchers tested the effects of FOUR DIFFERENT FDA approved drugs on a rat model of caloric restriction and stress-induced binge eating. In this study, the rats got to binge on a delectable mixture of nutella and rat chow = Yum!
They were testing these drugs is to validate their model as useful for predicting the efficacy of potential pharmaceuticals for the treatment of binge eating.
The authors divided the rats into four groups:
- non-restricted and not exposed to stress (NR + NS)
- restricted and not exposed to stress (R + NS)
- non-restricted and exposed to stress (NR + S)
- restricted and exposed to stress (R + S)
The rats then underwent an 8-day cycle that was repeated 3 times (see table below). The restricted groups (R + NS and R + S) got 67% of the regular food intake for the first four days of of the cycle whereas the non-restricted groups had unlimited food access during those days. On days 5 and 6, all animals got a yummy nutella mix for 2 hours in addition to their regular food. One days 7 and 8, all groups had unlimited access to food.
After the third cycle, the stressed groups (NR + S and R + S) were shown the nutella container and could smell the nutella, but could NOT access it. This procedure was argued to evoke a mild stress response akin to exposure to a “banned” food in humans, restraining from eating that taboo food, and then subsequently bingeing on it.
After this “stress” experience, all animals were exposed to a test session where they received free access to their regular food and the nutella paste. During the test session, ,the authors looked at the effects of this 24-day cycle on nutella/regular food intake, body weight, and stress hormone levels among the different groups.
WHAT DID THEY FIND?
- The restricted and stressed (R + S) group showed the highest overall intake of the nutella paste
- Both groups exposed to stress (R + S and NR + S) had higher stress hormone levels
- There were no differences in body weight among the four experimental groups
The body weight and stress hormone measures showed that it is the combination of food restriction and stress that contributed to binge eating in this model.
Next, the authors assessed the effects of four different drugs on binge eating in the four different rat groups. Two drugs were SSRIs: Fluoxetine (Prozac®) and Sibutramine (Reductil®, also a selective norepinephrine reuptake inhibitor), one was Topiramate (Topomax®, an anti-epileptic drug with some indications of reducing binge eating), and the final drug was the anxiolytic drug Midazolam (Ipnovel®, a benzodiazepine).
- Both SSRIs (Fluoxetine and Sibutramine) reduced food intake in all rat groups.
- The anti-epileptic Topiramate reduced binge eating ONLY in the restricted and stressed (R + S) group.
- The anxiolytic Midazolam had no effects.
Continuously evaluating the efficacy of animal models is immensely important to the field of drug development. Those of us at the “bench” need to engage in cross-talk with those at the “bedside” (i.e., clinic) to ensure that we have the most accurate interpretations of our outcomes and what their potential implications for the ED field may be.
And here’s where my questions for you come in:
1) SSRIs have mixed-efficacy in ED patients, but certainly some individuals DO benefit. However, is this model sensitive enough to have any predictive validity for novel therapeutics?
2) The use of SSRIs reduced food intake in ALL groups, not just those that were exposed to stress and food-restriction. Thus, could this drug act by curbing appetite in general? Wouldn’t this be the OPPOSITE of what we would want in a drug to treat eating disorders? Specifically, could the use of SSRIs potentially reinforce continued food restriction among a subset of eating disorder patients?
3) What (construct) is being measured here? Do you think this model adequately reflects binge eating in humans? The stressor is very food-specific, which may not correctly model the multitude of different precipitators of binge eating. Do you think this limits what we can conclude about the effects of the drugs on binge eating?
So, let me know what you think in the comments! And, of course, don’t hesitate to ask questions if anything is unclear.
Cifani, C., Polidori, C., Melotto, S., Ciccocioppo, R., & Massi, M. (2009). A preclinical model of binge eating elicited by yo-yo dieting and stressful exposure to food: effect of sibutramine, fluoxetine, topiramate, and midazolam Psychopharmacology, 204 (1), 113-125 DOI: 10.1007/s00213-008-1442-y