Gastric effects of cholecystokinin and its interaction with leptin on brainstem neuronal activity in neonatal rats.

Cholecystokinin (CCK) is a major gastrointestinal neuropeptide that is secreted in response to food ingestion. It is involved in the feedback regulation of gastric emptying and also modulates food intake. Leptin, a hormone that regulates food intake and energy balance, is secreted from adipose tissue, gastric mucosa, fundic glands, and other tissues. In a previous report we showed that gastric effects of leptin activated the nucleus tractus solitarius (NTS) neurons responding to gastric vagal stimulation. In this study, using the same in vitro neonatal rat preparation, we investigated the gastric effects of CCK and its interaction with leptin on NTS neurons receiving gastric vagal inputs. We observed that peripheral gastric effects of CCK (300 nM) produced a mean activation response of 271 +/- 3.9% compared with control level (100%) in 33 (60%) neurons tested (P <.01), and this response was abolished by a CCK-A receptor antagonist. A concentration-dependent effect of CCK (10 nM-1.0 microM) on NTS neuronal discharge frequencies was shown. We also observed that leptin (10 nM) applied to the stomach produced a mean activation response of 183 +/- 5.3% in 13 (50%) NTS units that responded to CCK (P <.01). Furthermore, we evaluated the combined effect of CCK and leptin in two groups of NTS neurons. Those NTS units that showed activation responses to both CCK (300 nM) and leptin (10 nM) had a subadditive effect that produced a mean activation response of 338 +/- 12.9% compared with the control level in all 10 (100%) neurons tested (P <.01). Eight (36%) of another 22 units that were not affected by either CCK (300 nM) or leptin (10 nM) alone had an activation response (151 +/- 5.2%; P <.05) when the same concentrations of CCK and leptin were applied together. Subsequently, by comparing the effects of CCK and leptin on a whole-stomach preparation to a partial-stomach preparation, we examined the area of the stomach in which gastric receptors contributed most to NTS unitary activity. We showed that the distal stomach containing the pylorus determined CCK gastric activity, whereas both the proximal and distal stomach are important for leptin's effect. Our data suggest that leptin modulates the potency of CCK signals that modify food intake in the neonatal rat.