The CCKB antagonist CI988 reduces food intake in fasted rats via a dopamine mediated pathway

Abstract

Studies have shown a reduction of food intake following peripheral and brain injection of CCK. However, it remains to be established whether endogenous central CCK is involved in the regulation of food intake. We investigated the role of central CCK in the regulation of food intake by pharmacological manipulation of the CCK(B) (CCK(2)) receptor system. Intracerebroventricularly (ICV) cannulated male Sprague Dawley rats were fasted for 24h and received an ICV injection of the CCK(B) receptor antagonist CI988 at a dose of 10 nmol or 49 nmol or vehicle. Another group received two consecutive ICV injections consisting of the corticotropin-releasing factor (CRF) receptor-1 (CRF(1)) antagonist, CP376395 (3 nmol) or the CRF(2) receptor antagonist, K41498 (2 nmol) alone, or followed by CI988 (49 nmol). Lastly, another group of rats received an intraperitoneal (IP) injection of the dopamine antagonist, flupentixol (~197 and ~493nmol/kg) alone, or followed by CI988 (49 nmol, ICV). Cumulative food intake was assessed for 11h. Vehicle injected rats showed a robust feeding response. CI988 at 49 nmol reduced food intake by 30% starting at 2h post injection. CP376395 and K41498 had no effect on food intake. Flupentixol injected IP at a dose of 197 and 493 nmol/kg alone did not modulate food intake whereas the higher dose blocked the CI988-induced reduction of feeding. During the dark phase, CI988 had no effect on food intake in unfasted rats. In summary, CCK(B) signaling is involved in the regulation of food intake after a fast likely by downstream dopamine signaling.