2‐Naphthalenesulphanyl‐L‐aspartyl‐2‐(phenethyl) amide (2‐NAP) and food intake in rats: evidence that endogenous peripheral CCK does not play a major role as a satiety factor

Abstract

1The demonstration that systemic administration of the CCKA receptor antagonist, devazepide, increases food intake in rats has provided the strongest support for the hypothesis that endogenous peripherally released cholecystokinin (CCK) acts as a satiety factor. However, interpretation of these results has been confounded by the fact that devazepide can enter the brain from the systemic circulation and may increase food intake by a central action. The present study was therefore undertaken to confirm the hypothesis that endogenous peripheral CCK is a satiety factor by investigating the effects of a novel CCKA receptor antagonist, 2-NAP, which is unlikely to cross the blood brain barrier, on food intake in rats.2 2-NAP (1-16 mg kg-', i.p.) had no significant effects on the intake of a test meal in rats.3 Pretreatment of rats with 2-NAP (2 mg kg-1, s.c.) abolished the inhibitory effects of exogenous peripheral CCK (5 ,ug kg-', i.p.) on food intake.4 In agreement with previous results, devazepide (50-200 ,ug kg-', i.p.) significantly increased the intake of a test meal in rats. 0 5 The observations that 2-NAP, which is unlikely to penetrate the blood brain barrier, had no effect on food intake, but that 2-NAP abolished the suppressant effect of exogenous peripheral CCK, suggest that endogenously released peripheral CCK is not important as a satiety factor in rats.

PEGylated cholecystokinin prolongs satiation in rats: dose dependency and receptor involvement

“…In our experimental system, administration of devazepide alone resulted in a significant 23 h augmentation of food intake compared to controls. This observation is consistent with the hyperphagia originally reported in a variety of animal species under a number of different feeding schedules and sustains the hypothesis that endogenous CCK plays a role in the control of food intake through the activation of CCK 1 receptors (Hewson et al , 1988; Ebenezer et al , 1990; Bado et al , 1991; Weatherford et al , 1993; Covasa and Forbes, 1994; Ebenezer and Baldwin, 1995). The present study also showed that coadministration of devazepide (100 μ g kg −1 ) with the PEGylated CCK 9 (6 μ g kg −1 ) completely abolished the anorectic effect of PEG‐CCK 9 over the 23 h measurement period, showing that CCK 1 receptors are involved in food intake reduction induced by PEGylated CCK 9 .…”

“…(2003) suggested that the ineffectiveness of A‐70104 in these studies of Ebenezer and Parrot could be ascribed to the small doses used. In the present study, we used a dose of 3 mg kg −1 of 2‐NAP, which is reported to be sufficient to block the effects of exogenous peripheral CCK (Ebenezer and Baldwin, 1995), suggesting that this dose should also be sufficient to block the effects of the endogenous peripheral CCK. Using concentrations of 2‐NAP up to 21 mg kg −1 , identical observations were made (data not shown).…”

“…Studies in a number of animal species indicate that pretreatment with devazepide (L‐364.718), a specific antagonist of both central and peripheral CCK 1 receptors, completely abolishes the inhibitory effects of exogenous CCK on food intake (Weller et al , 1990; Smith and Gibbs, 1992, 1994; Weatherford et al , 1992). Furthermore, systemic administration of devazepide increases meal size in several species (Hewson et al , 1988; Ebenezer et al , 1990; Bado et al , 1991; Reidelberger et al , 1991; Weatherford et al , 1993; Covasa and Forbes, 1994; Ebenezer and Baldwin, 1995). These results suggest that endogenous CCK, released from the small intestine during a meal, results in satiety via the activation of CCK 1 receptors.…”

“…These results suggest that endogenous CCK, released from the small intestine during a meal, results in satiety via the activation of CCK 1 receptors. Other studies have shown that systemic administration of the specific CCK 1 receptor antagonists, 2‐naphthalenesulphonyl 1‐aspartyl‐(2‐phenethyl) amide (2‐NAP) (Baldwin et al , 1994; Ebenezer and Baldwin, 1995) or A70104 (Ebenezer, 2003), which do not cross the blood–brain barrier (BBB) (Baldwin et al , 1994), does not increase meal size, although pretreatment with these drugs blocks the anorectic effect of intravenous CCK. These studies support the hypothesis that endogenous CCK plays a role in the regulation of food intake via activation of central CCK 1 receptors (Baldwin et al , 1998).…”

Electrophysiological Responses of Nucleus Tractus Solitarius Neurons to CCK and Gastric Distension in Newborn Lambs

“…In the rat and pig, peripheral injections of 2-NAP abolish the satiating effect of peripherally injected CCK (Ebenezer and Baldwin, 1995;Baldwin et al, 1994). 2-NAP unlike devazepide has no effect on the intake of test meals nor does it eliminates the reduction of food intake produced by intracerebroventricular injections of CCK-8S.…”