ABSTRACT
1School of Pharmacy, Pharmacology Unit, University of Camerino, 62032 Camerino (MC), Italy
2Neuroscience CEDD, GlaxoSmithKline, 37135 Verona, Italy
There is evidence supporting a role of the orexin system in the modulation of feeding behavior. Injection of orexin-A, into the lateral ventricle of rats, induces a dose-related increase in food intake that is blocked by pre-treatment with SB-334867, an orexin 1 receptor (OX1R) antagonist. Moreover, lateral hypothalamus orexin neurons are activated by cues associated with food.
In this work we tested GSK1059865, a selective OX1R antagonist; JNJ10397049, a selective OX2R antagonist, and SB-649868, a dual OX1/OX2R antagonist in a binge eating model in female rats recently described by Cifani et al. [1]. We used topiramate as a reference compound because it was shown to selectively block binge episodes in humans. The pharmacokinetic profiles of tested compounds were also investigated.
Results showed that SB-649868 did not affect feeding in rats with no history of restrictions and not exposed to stress (NR+NS). Conversely it selectively reduced highly palatable food (HPF) intake in rats previously exposed to 3 cycles of food restriction and then exposed to stress (R+S) (binge eating group). Stress was induced by preventing access to HPF for 15 min, while rats were able to see and smell it. After the stressful procedure the rats had free access to HPF and standard chow. JNJ10397049 did not affect HPF intake either in NR+NS or in R+S. The selective OX1R antagonist did not affected HPF intake in NR+NS but completely prevented the occurrence of binge eating in R+S. The present results indicated that orexin receptor antagonists selectivity prevent binge eating behavior and that this effect is mediated by OX1R. These findings suggest that OX1R may represent an interesting target for the pharmacological treatment of binge eating disorders.
[1] Cifani et al. (2009) Psychopharmacology 204(1):113-25