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OBJECTIVE Glucagon-like peptide-1 (GLP-1) receptor agonists, such as exendin-4, are being developed for the treatment of type-2 diabetes and obesity.However, treatment with exendin-4 is associated with nausea and sometimes emesis.Previously, we demonstrated that exendin-4 could lower blood glucose levels, induce emesis and c-fos in Sunus murinus.In the present studies, we examine the glucose-lowering and emetic action of exendin-4 in the ferret.METHODS Glucose tolerance test: Male ferrets (1.2-2.0 kg) were anaesthetized using pentobarbitone (40 mg· kg-1, i.p.).Then, they were injected with exendin (9-39) (300 nmol·kg-1, s.c.) or saline (0.5 ml·kg-1, s.c.).15 min later, exendin-4 (30 nmol·kg-1, s.c.) or saline (0.5 ml·kg-1, s.c.) were injected, followed by a glucose load (1.5g·kg-1, i.p.).Blood glucose levels were measured for up to 120 min.I.C.V study: A guide cannula was implanted into the 3rd ventricle of male ferrets (1.2-2.0 kg) under general anaesthesia.Seven days later, they were injected with exendin-4 (0.3-30 nmol, i.c.v.) or saline (15 μl, i.c.v.) and behaviour was recorded for 1 h.RESULTS Prior to drug administration, the basal blood glucose level was 5.2 ±0.4 mmol·L-1.The administration of glucose caused a progressive elevation of blood glucose in the saline-treated animals, which peaked at 30 min before decreasing gradually.Exendin-4 produced a 36.3% reduction in the AUC0-120 values (P < 0.05).Exendin (9-39) antagonized glucose lowering effect of exendin-4 (P <0.05), and exendin (9-39) alone increased AUC0-120 values by 31.0% (P < 0.05).Exendin-4 at 30 nmol, i.c.v, induced 88.2 ± 48.7 retches and 11.6 ± 6.8 vomits in 14.8 ± 9.2 episodes, following a median latency of 14.9 min (P < 0.05) ; lower doses did not induce emesis.Further, exendin-4 at 0.3-30 nmol, i.c.v, inhibited food intake (P < 0.05), but not water intake.CONCLUSION GLP-1 receptors are involved in emesis and feeding, and in modulating blood glucose levels in the ferret.