It has been proposed that cholecystokinin (CCK) released from the small intestine during a meal acts as a peripheral satiety factor, and it has been shown that systemic administration of the CCK₁ receptor antagonist devazepide increases food intake in experimental animals, lending support for the CCK-satiety hypothesis (see Baldwin et al., 1998). However, it is not inconceivable that systemic administration of the drug increases food consumption by a central action, as devazepide can cross the blood brain barrier to enter the brain from the systemic circulation (see Baldwin et al., 1998). In agreement with this view, it has been found that systemic administration of CCK₁ receptor antagonists that do not cross the blood brain barrier do not increase the food consumption (Ebenezer et al., 1995; Ebenezer, 2003). Moreover, it has also been shown that intracerebroventicularly (i.c.v.) administration of low doses of devezepide increase food intake in rats, indicating a role for brain CCK in the control of feeding behaviour (Ebenezer, 2002). The effects of systemic and central administration of 2-naphthalenesulphanyl-L-aspartyl-2-(phenethyl) amide (2-NAP), a selective CCK₁ receptor antagonist that does not easily enter the brain from the systemic circulation (see Baldwin et al., 1998), was used in this study to further clarify the role(s) of CCK in the control of feeding behaviour.

Experiment 1. Male Wistar rats (n=8; b. wt. 390 – 420g) that had been fasted for 20h were allowed free access to food in experimental cages for 30 min (oral pre-load). The food was then removed and, 30 min later, they were given access to food for a further 180 min. The rats were injected i.p. with either saline or 2-NAP (1 - 8 mg kg^-1) immediately after the oral pre-load. The amount of food consumed by the rats was measured at intervals over 180 min, as described previously (Ebenezer, 2003). A repeated measures design was used with each rat receiving all treatments; 3 days separated successive trials.

Experiment 2. Male Wistar rats (n=5, b.wt. 300 – 340g) were implanted with i.c.v. cannulae, as described previously (Ebenezer, 2002). A similar experimental protocol, as described for Experiment 1 was used, except that the rats were injected i.c.v. with either saline or 2-NAP (1, 10, or 100µg). The amount of food eaten at the end of a 60 min period was measured. At the end of the experiments, the accuracy of cannulae placement was verified (see Ebenezer, 2002). The data from both experiments were analysed by ANOVA and post-hoc Neuman Keul test.

The results obtained for Experiment 1 show that 2-NAP (1 - 8 mg kg^-1; i.p.) had no effects on food intake compared with controls at any of the measurement intervals over the 180 min test period. For example, mean food intake(g) ± s.e. mean at 120 min were as follows: saline 9.5 ± 1.4g, 2-NAP (1 mg kg^-1) 8.9 ± 1.5g; 2-NAP (2 mg kg^-1) 9.5 ± 1.6g; 2-NAP (4 mg kg^-1) 9.1 ± 1.0g, 2-NAP (8 mg kg^-1) 10.7 ± 1.4g. By contrast, i.c.v. administration of 2-NAP (1, 10 & 100 μg; Experiment 2) produced a dose related increase in feeding. The results obtained [mean food intake (g) ± s.e. mean] were as follows: Saline 8.2 ± 1.4g, 2-NAP (1 μg) 9.4 ±1.5g, 2-NAP (10 μg) 9.7 ± 1.9g, 2-NAP (100 μg) 8.6 ± 1.5g. Analysis of the data showed significant main effects of treatment (F_94,16) = 3.607, P<0.05). Post -hoc tests revealed that the 10 μg dose produced a significant increase in food intake (P<0.05).

The results of this study confirm and extend previous observations (Ebenezer et al., 1995; Ebenezer, 2002, 2003;) and lend further support for the notion that peripheral endogenous CCK is not important as a satiety factor, but that central endogenous CCK may play a physiological role in the regulation of food intake.

Baldwin, B.A. et al. (1998) Progress in NeuroBiology . 55, 477 - 507.
Ebenezer, I.S. (2002) Eur. J. Pharmacol . 441, 79 – 82.
Ebenezer, I.S. (2003) Eur. J. Pharmacol., 461, 113 - 118.
Ebenezer, I.S. et al. (1995) Br. J. Pharmacol., 116, 2371 - 2374.