Influence of Retrodipeptide Analogue of Cholecystokinin Tetrapeptide (GB-115) and Phenazepam on the Behavior of Rhesus Monkeys under Isolation Conditions.

Abstract

Introduction: The developed domestic retrodipeptide analogue of cholecystokinin tetrapeptide (CCK) (N-(6-phenylhexanoyl)-glycyltryptophan amide, or compound GB-115) with antagonistic properties in relation to CCK1 receptors has anxiolytic activity previously shown in preclinical and clinical studies. The aim of the study was to evaluate the anxiolytic effect of GB-115 as a tablet form with subchronic oral administration in comparison with phenazepam in nonhuman primates.

Materials and methods: The study was conducted on four male rhesus monkeys (Macaca mulatta) aged 5.7-6.7 years. After a 30-day adaptation to the conditions of individual caging, experiments were performed first with GB-115 (tablets of 0.001 g) and second with phenazepam (tablets of 0.0005 g). Both drugs were administered one at a time (7 days) and then two tablets each (7 days). Behavior was assessed by observing an object with registration according to the "Yes-No" principle of ethogram elements at the background periods, during the administration of the drugs, and after their withdrawal. The stress response was assessed using cortisol and dehydroepiandrosterone sulfate (DHEA-S) levels as biomarkers determined in the blood serum by enzyme immunoassay.

Results: GB-115 (0.001 g each) and phenazepam (0.001 g each) decreased the stay of the animals in the upper part of the cage compared to the background period, indicating decrease in stress response. GB-115 (0.002 g each) reduced the cortisol/DHEA-S ratio. Phenazepam dose-dependently decreased the level of cortisol in the blood serum without affecting the content of DHEA-S. Under administration of phenazepam (0.001 g each), a decreased cortisol/DHEA-S ratio was also observed.

Conclusions: A positive effect of GB-115 upon subchronic administration on the attenuation of the emotional stress response and the restoration of adaptive behavior in rhesus monkeys comparable to the effect of phenazepam was revealed, which confirms the possibility of using blockade of CCK1 receptors as one of the approaches for treating anxiety disorders.