Insights into the central pathways involved in the emetic and behavioural responses to exendin-4 in the ferret.
GLP-1 receptor agonists are utilised for the treatment of Type-2 diabetes but can be associated with undesirable effects of nausea and vomiting.



To investigate the role of GLP-1 receptors in mechanisms of emesis, behaviours indicative of nausea (BIN) and food intake in the ferret.



Exendin-4 (10 and 30nmol, i.c.v.) induced emesis, inhibited food intake, and increased the frequency of BIN. Increases in c-Fos in the brainstem, midbrain and forebrain occurred in animals exhibiting emesis; no activation of the brainstem occurred in animals not vomiting. Exendin-4 (10nmol, i.c.v.) when preceded by i.c.v. saline (15μl), was not emetic but induced BIN and inhibited food intake; exendin (9-39) (100nmol) reduced BIN only. c-Fos showed that consistent with the absence of emesis in saline/exendin-4 treated animals there was no increase in c-Fos in the brainstem, but it increased in midbrain and forebrain nuclei. Excepting the amygdala, exendin (9-39) was without efffect on the increases in c-Fos. Analysis of c-Fos data showed a positive linear relationship between midbrain and forebrain areas irrespective of the occurrence of emesis induced by exendin-4. In contrast, brainstem and midbrain c-Fos levels were positively correlated, but only in animals with emesis.



The brainstem is critical for exendin-4-induced emesis but suppression of food intake and BIN involves more rostral brain sites. Exendin-4-induced BIN and c-Fos activation of the amygdala are sensitive to exendin (9-39), whereas the suppression of food intake is not implicating separate control mechanisms for emesis and BIN.
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR. China.
Zengbing
Z
Lu
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR. China.
Chi-Kong
CK
Yeung
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR. China.
Ge
G
Lin
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR. China.
David T W
DT
Yew
Division of Biomedical Sciences, St George's University of London, London, UK.
P L R
PL
Andrews
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR. China; Brain and Mind Institute, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong, SAR. China. Electronic address: jar@cuhk.edu.hk.
John A
JA
Rudd
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002408:Catheters, Indwelling; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects / Q000502:physiology; D004639:Emetics / Q000494:pharmacology*; D000077270:Exenatide; D005289:Ferrets; D052216:Glucagon-Like Peptide 1 / Q000819:agonists / Q000378:metabolism; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009325:Nausea / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000494:pharmacology*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D014688:Venoms / Q000494:pharmacology*; D014839:Vomiting / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology
D004639:Emetics; D010455:Peptides; D016760:Proto-Oncogene Proteins c-fos; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide
Emesis; Exendin-4, exendin (9–39); Ferret; Glucagon-like peptide-1; Glucagon-like peptide-1 receptor; Nausea; c-Fos