Anxiogenic Effect of Cholecystokinin in the Dorsal Periaqueductal Gray

Systemic administration of cholecystokinin (CCK) fragments produces anxiogenic effects. The dorsal periaqueductal gray (dPAG) has been related to anxiety and panic reactions. The objective of this study was to investigate a possible anxiogenic effect of CCK-8 microinjected into the dPAG. At 10 min after the last microinjection (0.5 μl) into the dPAG male Wistar rats (N=7–17) were tested in the elevated plus-maze, an animal model of anxiety. The following treatments were tested alone or in combination: sulfated CCK-8 (CCK-8s, 0.5–1 μg), PD 135,158 (N-methyl-D-glucamine, 0.1 μg), a CCK-2 receptor antagonist, lorglumide (0.1–0.3 μg), a CCK-1 receptor antagonist. In addition, Fos immunohistochemistry was performed in rats (n=3–4) treated with CCK-8s (1 μg) alone or in combination with PD 135,158 (0.1 μg). CCK-8s produced anxiogenic-like effect, decreasing the percentage of time spent in open arm (saline=30.3±6.6, CCK 0.5 μg=15.2±1.8; CCK 1 μg=14.6±2.1). This effect was prevented by pretreatment with PD 135,158, but not by lorglumide. CCK-8s injected into the dPAG induced Fos immunoreactivity in several brain areas related to defensive behavior, including the PAG, median, and dorsal raphe nuclei, superior colliculus, lateral septal nuclei, medial hypothalamus, and medial amygdala. This effect was also prevented by pretreatment with PD 135,158. These results suggest that CCK-8s, acting on CCK-2 receptors, may modulate anxiety reactions in the dPAG.