Cholecystokinin-2 receptors modulate freezing and escape behaviors evoked by the electrical stimulation of the rat dorsolateral periaqueductal gray

Systemic injection of the cholecystokinin type 2 (CCK2) receptor agonist CCK-4 evokes panic attacks in humans and facilitates the expression of a panic-related defensive behavior, escape, in rats. Given the prominent role attributed to the dorsal periaqueductal gray (dPAG) in the pathophysiology of panic, this midbrain area has been assumed to be one of the key regions mediating these effects of CCK-4. However, only a few studies have directly investigated the role of dPAG CCK2 receptors in the regulation of panic-related behaviors. Even more disappointingly, the results of these investigations have been far from conclusive. In the present study we further addressed this issue by evaluating the effect of the intra-dorsolateral periaqueductal gray (dlPAG) injection of CCK-4 on two panic-related defensive behaviors, freezing and escape, evoked in male Wistar rats by the electrical stimulation of the dlPAG. The effects of CCK-4 (0.005-0.5 μg/0.2 μl) were compared to those caused by the local microinjection of the CCK2 receptor antagonist LY225910 (0.001-1.0 μg/0.2 μl). The results showed that whereas CCK-4 facilitated the expression of both freezing and escape behaviors, LY225910 had the opposite effect. Pretreatment with an ineffective dose of LY225910 prevented the panicogenic-like effect of CCK-4. These results strengthen the view that CCK2 receptors located in the dlPAG are involved in the regulation of panic-related behaviors and may mediate the effect of CCK-4 on panic.