Innovative pharmacological strategies for treatment of binge-type eating disorders

Binge eating (BE) episodes are a common behavioral feature of clinically diagnosed eating disorders, including Bulimia Nervosa (BN), Binge Eating Disorder (BED) and the binge/purge subtype of Anorexia Nervosa (AN). BE is characterized by uncontrollable, distressing eating of a large amount of highly palatable food (HPF) in a short period of time, accompanied by feeling of disgust, depression, being guilty. Recent data indicate that BE is the most common eating disorder, affecting approximately 5% of the USA population; BE may greatly contribute to obesity, Medications that at present have been reported to reduce BE in clinical studies, like topiramate or sibutramine, are associated with a variety of adverse side effects, which represent a serious problem during chronic treatment. Fluoxetine has been approved by the Food and Drug Administration for BN, but evidence for its efficacy is inconclusive. Hence, BED and BN represent a still largely unmet medical need. Well-characterized animal models are necessary to study the neuro- and psychobiology of BE, the motivational alterations associated with compulsive eating behaviors, as well as to develop novel treatment strategies. According to the hypothesis that dieting and stress are key etiological determinants of BE, a new animal model of BE has been recently developed in female rats at the School of Pharmacy of the University of Camerino (Cifani et al. 2009), in which BE episodes are evoked by 3 cycles of food restriction/re-feeding followed by stress. Stress is elicited by exposing rats to HPF, but preventing them from having access to it for 15 min. Since a certain degree of variability was observed in the BE response in the Cifani model, a preliminary interest of my research program was to understand the causes of this variability in order to improve the reliability of the method. In particular, it was evaluated whether the ovarian cycle of female rats may be responsible for the observed variability. It was found that BE episodes do not occur during the estrus phase of the ovarian cycle and the observed variability in the BE response can be almost completely abolished if female rats in estrus are not included in the statistical evaluation. Then, the effects of several compounds, targeting stress and CRF mechanisms, were evaluated on this BE model: natural anti-stress products such as dry extracts of Rhodiola rosea and of Hypericum perforatum, the CRF-1 receptor antagonist R121919, Corticosterone (CORT), the CORT synthesis inhibitor metyrapone, and finally Nociceptin/orfanin FQ (N/OFQ, a functional CRF antagonist). Using the same BE model, orexin receptor antagonists were investigated since orexin appear to be involved both in stress and in reward mechanisms. Lastly, based on the observation that drugs that affect compulsive alcohol consumption can also influence BE, a further study was carried out to assess the effect on BE of A2A adenosine receptors (A2AARs) agonists, that have been shown to suppress voluntary alcohol intake and alcohol self-administration in alcohol- preferring rats. The results obtained confirmed that the combination of stress and repeated episodes of food restriction is able to induce in female rats a pronounced BE response for HPF. The natural extract of Rhodiola rosea, as well as its active principle salidroside, exerted a pronounced and selective suppression of HPF intake in rats expressing BE, apparently reducing the response to stress. Also Hypericum perforatum extracts selectively reduced BE, but without modifying serum CORT levels; thus their effect on BE may be related to suppression of addictive-like behaviors, rather than to anti-stress activity. The CRF-1 receptor antagonist R121919 completely abolished BE in the experimental model adopted, without affecting HPF intake in the groups of rats that did not express BE. These findings suggest that CRF-1 receptor antagonists may represent very interesting agents, endowed with marked and highly selective effect, for the pharmacotherapy of bingeing-related eating disorders. CRF may likely exert its role on BE in extrahypothalamic sites, since CORT, the hormone released by hypothalamic-pituitary axis activation, failed to evoke BE in rats exposed to cycles of food restriction/re-feeding and metyrapone, a CORT synthesis inhibitor, failed to suppress BE. On the other hand, the functional CRF antagonist N/OFQ was not able to evoke a relevant suppression of BE. Following repeated food restrictions, an increase in responsiveness to the hyperphagic effect of N/OFQ was found, which may account for its failure to suppress BE. Interestingly, cycles of food restriction/re-feeding increase the response to several orexigenic mechanisms (in the present study this was observed for N/OFQ and for NPY); this phenomenon may be responsible for failure of dieting cycles as a strategy to reduce body weight and it may predispose to binge type-eating disorders. On the other hand, OX1R blockade selectively reduced BE for HPF without affecting standard food pellet intake, and could represent a novel interesting strategy for the treatment of BE related disorders. Further studies are necessary to evaluate their mechanism of action of OX1R antagonists, in particular whether their effect may be mediated by interaction with stress or reward mechanisms. A2AAR agonists proved to exert a rather general effect on food intake, suppressing HPF intake not only in animals expressing BE, but also in controls. Moreover they inhibited also the homeostatically driven intake of food pellets in response to food deprivation. In relation to the finding that A2AARs influenced D2 DA receptors, it may be speculated that the suppressive effect on BE of A2AAR agonists tested may be due to interference with DA mechanisms. In conclusion, the experimental model adopted to evoke BE, which is endowed with face, contruct and predictive validity, was made highly reliable and reproducible by selecting the experimental animals on the basis of the ovarian cycle. The studies carried out in this model have allowed the evaluation of several pharmacological agents, that proved to be highly effective in suppressing BE. Particularly pronounced and selective effects were evoked by the CRF-1 receptor antagonist and the OX1R antagonist tested, that evoked effects of clear interest in the perspective of treating binge-type eating disorders. Interestingly, also the herbal products Rodiola rosea and Hypericum perforatum proved to be very effective, but the receptor mechanisms mediating their effects remain to be elucidated.