Although it is known that panic attacks are triggered by the cholecystokinin fragment CCK4, the specific involvement of peripheral or central cholecystokinin CCK receptors in various adaptive processes such as emotion, memory and anxiety has yet to be demonstrated. With this aim, we have investigated the biochemical and pharmacological effects resulting from the administration of BC264, a highly potent and selective CCK-B agonist able to cross the blood-brain barrier. Very low doses of BC264 (microg/kg i.p.), increased the exploration of animals submitted to an unknown territory but were devoid of anxiogenic properties in the elevated plus maze. BC264 increased locomotion and rearings of rats newly placed in an open field and improved their spontaneous alternation in a Y-maze. The use of vagotomized animals showed that the increased alternation induced by BC264 did not require an intact vagus nerve, unlike the locomotor activation. These behavioural effects, prevented by the prior i.p. administration of the CCK-B antagonist L-365,260 but not by the CCK-A antagonist L-364,718, were shown to depend on dopaminergic systems, since they were blocked by D1 (SCH23390, 25 microg/kg i.p.) or D2 (sulpiride, 50 or 100 mg/kg i.p.) antagonists. In addition, bilateral perfusion in freely moving rats of BC264 at pharmacologically active doses, using a newly designed microdialysis system, was found to increase the extracellular levels of DA, DOPAC and HVA in the anterior part of the nucleus accumbens. These results show that activation of CCK-B receptors by BC264 does not produce anxiogenic-like effects but appears to improve motivation and attention, whereas other CCK-B agonists such as BocCCK4 induce anxiogenic responses. Several explanations, including the existence of different sub-sites of the CCK-B receptor, could account for these differential effects.

Antagonists of cholecystokinin-B (CCK-B) receptors have been shown to alleviate CCK4-induced panic attacks in humans and to potentiate opioid effects in animals. The clinical use of these compounds is critically dependent on their ability to cross the blood-brain barrier. In order to improve this property, new, peptoid-derived CCK-B antagonists, endowed with high affinity, selectivity, and increased lipophilicity have been developed. The affinity and selectivity of these compounds have been characterized in vitro and in vivo using guinea pig, rat, and mouse. Most of these compounds proved to be selective for the CCK-B receptor, the most potent analog, N-[N-[(2-adamantyloxy)carbonyl]-D-alpha- methyltryptophanyl]-N-[2-(4-chlorophenyl)ethyl]glycine (26A), having a Ki value of 6.1 nM for guinea pig cortex membranes in vitro and a good selectivity ratio (Ki CCK-A/Ki CCK-B = 174). Furthermore, the in vivo affinity of 26A for mouse brain CCK-B receptors, following intracerebroventricular injection at different concentrations, was found to be 10 nmol. Using competition experiments with the specific CCK-B ligand [3H]pBC 264, compound 26A was shown to cross the blood-brain barrier (0.2%) after intraperitoneal administration in mice. This compound is therefore an interesting pharmacological tool to further elucidate the physiopathological role of endogenous CCK.

No abstract