Cholecystokinin-induced anxiety in rats: relevance of pre-experimental stress and seasonal variations

Objective: To examine the influence of pre-experimental stress on the anxio genic-like action of caerulein, an agonist of cholecystokinin (CCK) recepto rs. Differences in the anxiety levels of rats in summer and winter, and the role of CCK in these behavioural alterations, were also examined. Design: Prospective animal study. Interventions: Male Wistar rats were injected wit h the CCK agonist caerulein, or the CCK antagonists L-365,260 or devazepide , after being exposed to pre-experimental stress (handling and isolation). Outcome measures: Performance in the plus-maze model of anxiety; serum leve ls of prolactin, thyrotropin and growth hormone; brain density and affinity of dopamine D-2, serotonin 5-HT2 and CCK receptors. Results: Caerulein (5 mu g/kg, subcutaneous injection) caused the strongest action in animals bro ught to the experimental room immediately before the experiment and kept in isolation after the administration of caerulein. Caerulein did not cause a ny reduction of exploratory activity in rats made familiar with the experim ental room and kept in the home-cage after the injection of the CCK agonist . The anti-exploratory action of caerulein in stressed rats was reversed by the CCK antagonist L-365,260 (100 mu g/kg, intraperitoneal injection), dem onstrating the involvement of the CCK8 receptor subtype. In addition, seaso nal fluctuations occur in the exploratory activity of rats; such activity w as much lower in July than in November. The rats displaying the reduced exp loratory activity had an increased number of CCK receptors in the frontal c ortex and hippocampus. Simultaneously, the density of serotonin 5-HT2 recep tors in the frontal cortex, but not that of dopamine D-2 receptors in the s triatum, was elevated. The blood level of growth hormone was also higher in July. Conclusions: The anti-exploratory action of caerulein appears to be dependent on the pre-experimental stress of rats. Moreover, the seasonal va riations of exploratory behaviour of rats are evident in the plus-male mode l of anxiety. The reduced exploratory activity in summer appears to be rela ted to the elevated density of CCK and 5-HT2 receptors in the brain.