Anxiogenic-like action of caerulein, a CCK-8 receptor agonist, in the mouse: influence of acute and subchronic diazepam treatment

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Abstract
Effects of caerulein, a cholecystokinin octapeptide (CCK-8) receptor agonist, on exploratory activity of mice were investigated. Exploratory and locomotor activity of animals were measured using elevated plus-maze and open field tests. The systemic administration of caerulein at nonsedative doses (100 ng/kg-1 µkg i. p.) resulted in a significant decrease in the exploratory activity of mice. This effect was completely blocked by proglumide, a CCK-8 antagonist (15 mg/kg i. p.), indicating the participation of CCK-8 receptors. Acute treatment with low doses (0.1–0.75 mg/kg i. p.) of diazepam did not attenuate the anxiogenic-like effect of caerulein, but at more high doses of diazepam the coadministration depressed locomotor activity in mice. After subchronic diazepam treatment (2.5 mg/kg once a day, 10 days, i.p.) tolerance was developed toward the sedative effect of diazepam, and 72 h after withdrawal of the drug the animals showed increased anxiety in the plus-maze test. 30 min after the last injection procedure the anxiogenic-like effect of caerulein (500 ng/kg i. p.) on exploration was absent in both diazepam or vehicle groups. However, 72 h after the last pretreatment injection caerulein (500 ng/kg i. p.) reduced significantly the exploratory activity in control group, whereas it was inactive after diazepam withdrawal. The results obtained in this study support the hypothesis that endogenous CCK-8 an CCK-8 receptors are involved in the neurochemistry of anxiety and the anxiolytic action of benzodiazepine tranquillizers.