Delayed stress-induced increase in tissue level of cholecystokinin in rat prefrontal cortex: modulation by microdialysis probe implantation and systemic ketamine

In the brain, the neuropeptide cholecystokinin (CCK) appears to be involved in the mediation of stress responses. Here we provide new evidence that mi ld stress induces long-term changes in CCK-like immunoreactivity (CCK-LI) i n the prefrontal cortex (PFC). The changes in CCK-LI show a biphasic patter n, with a decrease 20 min after and an increase 8 h after mild stress. Thes e changes seem to be region specific. Measurement of CCK mRNA in prefrontal cortex neurons 4 or 8 h after the stress stimulus did not reveal changes i n mRNA levels, suggesting that afferent CCK-containing neuron terminals may be more affected than local cortical CCK-ergic neurons. Furthermore, treat ment with the glutamate NMDA receptor antagonist ketamine, led to more pron ounced decreases in CCK-LI observed within 20 min after mild stress and cou nteracted the stress induced increase in cortical CCK-LI levels observed at 8 h. Implantation of a microdialysis probe in the PFC affected the respons e to mild stress, with no significant decrease in the CCK-LI level 20 min a fter, and attenuated reactivity to stress 8 h after the saline injection. O ur results indicate that a mild stressful stimulus such as an intraperitone al saline injection may have long-lasting effects on CCK-ergic transmission in the PFC. The use of microdialysis to study stress induced in vivo CCK-L I release in awake animals may, however, be significantly compromised by th e impact of the microdialysis probe implantation on CCK-ergic mechanisms in the PFC. In addition, we hypothesize that subanesthetic doses of the psych otomimetic drug ketamine interfere with CCK-ergic mechanisms in the PFC dur ing stress. (C) 2001 Elsevier Science BV All rights reserved.