It’s often interesting to look over the scientific literature, and to see, for lack of a better term, “fashion trends”. Not what style of kahkis the PIs are wearing this fall, but rather neurotransmitters, techniques, behaviors, or models that you can watch go in and out of fashion. There are lots of different reasons for why this occurs, sometimes a new, better model comes along, sometimes the technique is not a versatile as first thought, sometimes the new neurotransmitter field gets extremely “crowded” and people feel they need to branch out. But it’s interesting to see things wax and wane, and to try and see if you can predict where some things are going. For example, when it first appeared on the scene, the technique of optogenetics (stimulating cells to fire by hitting them with light, because you have infected them with a light sensitive channel) was the new hot thing. Optogenetics is still very “now”, and promises to stick around for a bit, as the flexibility of the technique is still being tested. Knockout mice, on the other hand, though they were wildly popular (and are still), are being replaced with things like targeted knockouts of genes that are localized to specific regions, or inducible knockouts that will only become knockouts when you stimulate the system with something in the diet. It’s a more specific technique and so the older technique is gradually becoming less popular.
It works the same way for neurotransmitters, the chemicals released between neurons to convey messages. And I’ve been noticing a new one that I think is going to be an up and comer. This chemical is called orexin (or hypocretin, two groups characterized it at the same time and the name war has continued for years now. It looks like orexin is winning out, for while hypocretin is more functionally accurate…orexin sounds a lot better and is easier to say). Orexin was originally noticed due to two main behaviors: sleep, and appetite. Orexin is a powerful mediator of something called arousal (what you might also call attention or wakefulness, though it’s not quite the same as either). In fact, the most common form of narcolepsy is due to a lack of orexin in the brain.
(Aww, poor doggie)
But orexin is also extremely important as a mediator of appetite. Giving orexin will increase craving for food, and giving a hormone like leptin (a signal of fullness), inhibits orexin.
And this means that orexin could be a new target for problems associated with appetite, particularly things like binge eating.
Piccoli et al. “Role of Orexin-1 Receptor Mechanisms on Compulsive Food Consumption in a Model of Binge Eating in Female Rats” Neuropsychopharmacology, 2012.
As you might know if you have read some of my previous posts, a drug/neurotransmitter/chemical is only as good as its receptor. While increasing levels of a chemical in the brain is one thing, unless they have a receptor to act upon, nothing will happen. And WHICH receptors they act upon determine the potential effects.
In the case of orexin, there are two types of receptors, the 1 and the 2. The authors of this study wanted to look at how blocking these receptors might change palatable (that’s tasty) food intake in their binge eating rat model.
First, of course, you have to make the binge eating rats. For this they used female rats (which pleased me very much, as I think people don’t study females enough, and when dealing with issues of food intake, it is particularly important), and exposed them to a highly palatable food.
Side note: this is one of my favorite parts about writing up scientific methods. In writing up all the things you did, you have to make it so people can recreate the experiment (theoretically), and this means telling people where you got everything. So methods sections involve everything from highly sensitive measurement instruments…to Nutella. In this case “The HPF [highly palatable food] was a paste prepared by mixing Nutella (Ferrero, Alba, Torino, Italy) chocolate cream (5.33 kcal/g; 56%, 31%, and 7% from carbohydrate, fat, and protein, respectively), grounded food pellets (4RF18; Mucedola; Settimo Mila-nese), and water in the following weight/weight percent ratio: 52% Nutella, 33% food pellets, and 15% water. ”
The female rats were exposed to this palatable food…but not permitted to eat it. They were allowed to smell it and ALMOST to touch it. This caused the rats a certain amount of frustration and stress, and when exposed to the actual nutella mixture, they will then binge eat on it, much more than animals seeing nutella for the first time.
They then tested for dose and administered three different orexin receptor antagonists, one specific for orexin receptor 1, one specific for orexin receptor 2, and one that hit both 1 and 2.
Here you can see the results for the general antagonist. You can see that when the drug is on board (the dark dots), the rats binge ate LESS than in the control condition. In fact, the drug worked as well as topiramate, a current antiepileptic drug prescribed sometimes for binge eating.
Here we have the results for just the orexin receptor 1 antagonist. You can see that it also reduced food intake in the binge eating rats.
And here we have the results for the orexin receptor 2 specific antagonist, which did NOT decrease food intake.
So it looks like the orexin receptor 1 antagonist is the best bet for reducing food intake, but…what about arousal?
As I mentioned before, orexin plays an extremely important role in arousal. Giving orexin general antagonists produces major increases in sleep. So the general antagonist is out. The orexin 2 receptor antagonist also produced a significant increase in sleep. But the orexin 1 antagonist was able to reduce binge eating WITHOUT increasing sleep, making the orexin 1 receptor a potentially ideal target for reducing binge eating.
Of course there is a major difference between this model of binge eating in rats and binge eating in humans, but I think that this study does have some interesting implications. After a long time of binge eating, many binge eaters show changes in leptin sensitivity. Leptin is a hormone that signals fullness, and which inhibits the release of orexin. So it would be interesting to see if the patients who are insensitive to leptin could respond to a direct orexin receptor antagonist, or if their orexin receptor levels are changed due to the binge eating itself. There is a lot more work to do, but this is an up and coming molecule, and the work is just beginning. From narcolepsy to appetite, I begin to wonder where orexin will go next.
Piccoli L, Micioni Di Bonaventura MV, Cifani C, Costantini VJ, Massagrande M, Montanari D, Martinelli P, Antolini M, Ciccocioppo R, Massi M, Merlo-Pich E, Di Fabio R, & Corsi M (2012). Role of orexin-1 receptor mechanisms on compulsive food consumption in a model of binge eating in female rats. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 37 (9), 1999-2011 PMID: 22569505
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