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 (1.5 g·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 AUC_0-120 values (P<0.05). Exendin (9-39) antagonized glucose lowering effect of exendin-4 (P<0.05), and exendin (9-39) alone increased AUC_0-120 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.