The concentrations and contents of vasoactive intestinal peptide (VIP) and cholecystokinin (CCK) in the brain and of these peptides along with secretin and glucagon-like immunoreactivity (GLI) in the gut were compared in a group of 16 5-day fasted adult Sprague-Dawley rats with the corresponding peptides in a group of 16 nonfasted littermates. The mean weight of the fasted rats at the beginning of the study was 263 Â± 10 g (Â±SEM) and was 177 Â± 7 g before killing, for a net loss of 33% of initial body weight; the 16 fed rats increased their mean weight from 225 Â± 11 to 284 Â± 12 g, for a net gain of 12%. During the 5-day fast there was no change in the weight of the cortex, hypothalamus, or brain stem. However, the weight of tissues from the gut decreased to about half the weight of the corresponding tissues in the fed animals. There was no significant change in brain VIP or CCK. VIP content in the gut was unchanged. However, because of the decrease in organ weight, its concentration almost doubled. Secretin concentrations in the gut of fasted rats did not change significantly, but organ contents fell to about half. The gut content of GLI also fell by half or more. The concentrations of CCK in methanol extracts of the duodenum and jejunum remained relatively constant, but those in acid extracts fell by 40% in the fasted animals. This represents an approximately 70% decrease in organ content of CCK. These findings are interpretable as demonstrating that during a prolonged fast neuronal CCK and VIP are well conserved, but endocrine CCK, secretin, and GLI are markedly decreased because of loss of intestinal mucosa.