Additive feeding inhibitory and aversive effects of naltrexone and exendin-4 combinations

OBJECTIVE: One developing strategy for obesity treatment has been to use combinations of differently acting pharmacotherapies to improve weight loss with fewer adverse effects. The purpose of this study was to determine whether the combination of naltrexone, an opioid antagonist acting on the reward system, and exendin-4, a glucagon-like peptide 1 (GLP-1) agonist, acting on satiety signaling, would produce larger reductions in food intake than either alone in rats. Because the anorectic potencies of both compounds have been associated with nausea and malaise, the influence of these drug combinations on the acquisition of a conditioned taste aversion (CTA) was also determined. METHODS: In Experiment 1, the acute anorectic effects of naltrexone (0.32–3.2 mg/kg; IP) and exendin-4 (1–10 µg/kg; IP) were assessed alone or in combination. Combinational doses were further investigated by the repeated daily administration of 1 mg/kg naltrexone + 3.2 µg/kg exendin-4 for 4 days. In Experiment 2, both compounds alone or in combination were used as unconditioned stimuli in a series of CTA tests. RESULTS: Naltrexone and exendin-4, alone or in combination, suppressed food intake in a dose dependent fashion, and the interaction on food intake between naltrexone and exendin-4 was additive. In the CTA paradigm, naltrexone (1 mg/Kg) alone did not support acquisition, whereas a CTA was evident with doses of Ex-4 (1 or 3.2 µg/Kg). Combinations of naltrexone and exendin-4 also resulted in a more rapid and robust acquisition of a CTA. CONCLUSION: Given that the Nal and Ex-4 combination produces additive effects on not only food intake reduction but also food aversion learning, this specific drug combination does not have the benefit of minimizing the adverse effects associated with each individual drug. These data suggest that it is necessary to evaluate both the positive and adverse effects at early stages of combinational drug development.