The behavioural properties of CI‐988, a selective cholecystokinin_B receptor antagonist

Abstract

1 The behavioural effects of a selective cholecystokininB (CCKB) receptor antagonist CI-988 were investigated in rodents. 2 In three rodent tests of anxiety (rat elevated X-maze, rat social interaction test and mouse light/dark box) CI-988 over the dose range 0.001-I0.Omgkg 1, (i.p.) produced an anxiolytic-like action. The magnitude of this effect was similar to that of chlordiazepoxide (CDP). In contrast, the selective CCKA receptor antagonist, devazepide, was inactive. CI-988 also showed anxiolytic-like action in the rat conflict test but the magnitude of this effect was about 2.5 fold less than that of CDP. 3 Central but not peripheral administration of the selective CCKB receptor agonist, pentagastrin, like FG 7142, produced an anxiogenic-like action. 4 The pentagastrin-induced anxiety was dose-dependently antagonized by CI-988, whereas devazepide was inactive. However, ten times higher doses of CI-988 were required to block a similar action of FG 7142. 5 In contrast to CDP, CI-988 up to 3000 fold higher doses than those inducing anxiolysis was inactive in tests measuring sedation and ataxia. It also failed to antagonize pentylenetetrazol-induced tonic seizures. Furthermore, CI-988 did not interact with alcohol or barbiturates. Thus, CI-988 appears to be an anxioselective compound. 6 The anxiolytic-like action of CDP in the rat elevated X-maze was dose-dependently antagonized by flumazenil. In contrast, the benzodiazepine receptor antagonist failed to block a similar effect of Thus, CI-988 shows anxiolytic-like activity in several animal models of anxiety. The anxiolytic-like effect of CI-988 involves a novel mechanism of action, that is likely to be mediated by selective antagonism of the brain CCKB receptor. It is suggested that CI-988 should have a better side-effect profile in man than the benzodiazepines.

Activation of Amygdala CholecystokininBReceptors Potentiates the Acoustic Startle Response in the Rat

“…Conversely, systemic administration of the CCK B receptor antagonist L-365,260 attenuates fear-potentiated startle in rats (Josselyn et al, 1995a). These results are consistent with the anxiogenic and anxiolytic effects of systemically administered CCK B agonists and antagonists, respectively, in a range of behavioral paradigms including the elevated plus maze, light-dark box, punished responding, and social interaction (see, for example, Hughes et al, 1990;Harro and Vasar, 1991;Rataud et al, 1991;Singh et al, 1991;Männistö et al, 1994;Rex et al, 1994). These studies suggest that CCK B receptors mediate a constellation of behaviors associated with "anxiety" (see, for example, Harro et al, 1993).…”

“…Because systemically and i.c.v. administered CCK B agonists produce a broad range of autonomic and behavioral changes associated with "anxiety" (Singh et al, 1991;Harro et al, 1993;Belcheva et al, 1994), it is possible that the activation of amygdala CCK B receptors may result in the expression of a large number of behavioral and autonomic changes associated with "anxiety" or "fear." Consistent with this proposal is the finding that endogenous CCK-4 levels are elevated in the amygdala in rats after exposure to a predatorscented cloth (Pavlasevic et al, 1993).…”

Behavioral Profile of CCK2 Receptor- deficient Mice

“…These results appear striking since CCK2 receptors activation (especially the CCK2a subtype) by CCK agonists has been shown to be involved in stress-related behaviors leading to anxiogenic-like responses in mice (Harro et al 1993;. In addition, most of the studies have shown that the blockade of CCK2 receptors by selective antagonists induces anxiolytic-like responses in rodents (Rataud et al 1991;Singh et al 1991;Derrien et al 1994; see also reviews in Harro et al 1993;Shlik et al 1997;Daugé and Léna 1998). Therefore, the lack of behavioral modifications observed with CCK2 receptor-deficient mice, could be related to unknown compensatory processes.…”

Benzodiazepine/cholecystokinin interactions at functional CCK receptors in rat brain

“…Iontophoretic application of the watersoluble benzodiazepine, flurazepam, produced a selective block of CCK-induced increases in firing rate of CAl and CA3 hippocampal neurones in vivo (Bradwejn & De Montigny, 1984), an effect that was reversed by application of flumazenil. They proposed that this selective block of CCK responses by benzodiazepines acting via neuronal benzodiazepine receptors could account for the anxiolytic effects of these drugs, which is made more interesting by recent evidence that CCK11 antagonists are also potent anxiolytics (Hughes et al, 1990;Singh et al, 1991). Benzodiazepine inverse agonists have been shown to induce panic (Dorrow et al, 1983;Baldwin & File, 1988;Little, 1991).…”