Evidence for an involvement of the brain cholecystokinin B receptor in anxiety.

Abstract

The effect of neuropeptide cholecystokinin (CCK) receptor agonists and antagonists was examined in the rat elevated X-maze model of anxiety. The selective CCK-B receptor antagonists CI-988 (PD 134308) and L-365,260 produced anxiolytic-like effects, whereas MK-329, a CCK-A receptor antagonist, was respectively less potent by factors of 313 and 200. The intracerebroventricular administration of the nonselective CCK receptor agonist caerulein or the selective CCK-B receptor agonist pentagastrin increased dose dependently the level of anxiety. CI-988 dose dependently antagonized the anxiogenic response to pentagastrin but not that induced by pentylenetetrazol. These results strongly suggest that activation of the brain CCK-B receptor induces anxiety and that selective antagonists of this receptor represent a separate class of anxiolytic agents.Although originally described as a hormone in the gastrointestinal tract (1), cholecystokinin (CCK) also has been shown to be present in high concentrations in certain neurones ofthe brain (2), where it exists as the octapeptide CCK-8 in the sulfated (CCK-8S) and desulfated forms (3, 4). Receptors for CCK have been divided into two types: (i) the CCK-A receptor that is blocked selectively by L-364,718 and is found in peripheral tissues as well as discrete brain areas (6, 7), and (ii) the CCK-B receptor that is present throughout the brain (6) and is characterized by a high affinity for the novel antagonists CI-988 (PD 134308) and L-365,260 (8, 9). The CCK-B receptor is similar or identical to the peripheral gastrin receptor (9). CCK is present in high concentrations in the limbic system (10), an area involved in the control of emotion and anxiety. Furthermore, in some neurones CCK coexists with other neurotransmitters including y-aminobutyric acid (GABA) (11,12), and agents that modify GABAergic neurotransmission in the brain (13)-for example, benzodiazepines-possess anxiolytic properties (14). These observations prompted us to study the role of CCK in anxiety, and recently we reported that a CCK receptor antagonist, CI-988, produces anxiolytic effects in a number of animal models of anxiety (8). However, this study has raised several important MATERIALS AND METHODSAnimals. Male hooded Lister rats (200-250 g) were obtained from Olac (Bichester, U.K.). Animals were housed in groups offive under a 12-hr light/dark cycle (lights on at 0700) with food and water ad libitum.Implantation of Intracerebroventricular (i.c.v.) Cannulas. For i.c.v. administration, rats were anesthetized by using a mixture of diazepam (2.5 mg/kg of body weight, i.p.) and Hypnorm (0.315 mg of fentanyl citrate and 10 mg of fluanisone per ml; 0.2 ml/kg). A 22-gauge stainless-steel guide cannula was implanted unilaterally by using a Kopf stereotaxic frame [anterior-posterior = 8.2 mm anterior of interaural line; lateral = +1.4 mm; dorsoventral = 6.6 mm dorsal to the interaural line according to the atlas of Paxinos and Watson (18)]. Animals were allowed 5-7 days to recover from surgery before behav...

Significant Increase in the Aggressive Behavior of Transgenic Mice Overexpressing Peripheral Progastrin Peptides: Associated Changes in CCK2 and Serotonin Receptors in the CNS

“…Evidence strongly suggests that gastrin and CCK are related to anxiogenic effects, which are mediated by CCK 2 R (Bradwejn, 1993;Rehfeld, 2000;Singh et al, 1991). The increased brain CCK level was reported in a rat model of anxiety (Pavlasevic et al, 1993).…”

GABAergic interneurons are the targets of cannabinoid actions in the human hippocampus

“…CCK has been shown to enhance memory formation by acting on hippocampal neurons, and have strong anxiogenic effects, whereas cannabinoids interfere with memory formation and the endogenous tone they mediate may alleviate anxiety. 17,32,37,41 One may argue that the magnitude of suppression of GABA release (ϳ50%) is much higher than the number of CCK-containing interneurons in the hippocampus estimated to represent only 10-20% of all hippocampal interneurons in the rat. Indeed, not all CB1-containing interneurons expressed CCK (see Table 1 for details).…”

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

“…A standard elevated X-maze (Handley & Mithani, 1984;Pellow et al, 1985) was automated as previously described (Costall et al, 1989b;Singh et al, 1991a). However, to measure anxiogeniclike actions the total entries and time spent on the open arms was measured …”