Peptides 25 (2004) 1935–1941 Systemic and intra-dorsal periaqueductal gray injections of cholecystokinin sulfated octapeptide (CCK-8s) induce a panic-like response in rats submitted to the elevated T-maze Janaina Menezes Zanoveli, Cristina Ferreira Netto, Francisco Silveira Guimar˜ aes, H´ elio Zangrossi Jr. ∗ Department of Pharmacology, School of Medicine, University of S˜ ao Paulo, 14049-900 Ribeir˜ ao Preto, SP, Brazil Received 15 April 2004; received in revised form 23 June 2004; accepted 24 June 2004 Available online 11 August 2004 Abstract The neuropeptide cholecystokinin (CCK) has been implicated in fear and anxiety. CCK is found in the CNS in several molecular forms such as the tetrapeptide (CCK-4) and, mainly, the sulfated octapeptide (CCK-8s) fragments. Administration of CCK-4 induces panic attacks in humans and increases the expression of different anxiety-related behaviors in laboratory animals. The effects of CCK-8s on fear and anxiety are less straightforward and seem to be influenced, among other factors, by the route of the peptide administration and the animal model employed. In other to further investigate the role of CCK-8s in fear and anxiety, in the present study we analyzed the effect of CCK-8s in male Wistar rats submitted to the elevated T-maze. This animal model of anxiety was developed in order to separate generalized anxiety (inhibitory avoidance) and panic-like (escape) responses in the same rat. The effect of CCK-8s in this test was also investigated after injection of the peptide into the dorsal periaqueductal gray (DPAG). This brainstem area is rich in CCK receptors and has consistently been implicated in the mediation of fear and anxiety responses. The results showed that both the intraperitoneal and intra-DPAG injections of CCK-8s potentiated one-way escape behavior, suggesting a panicogenic action. In contrast, the injection of the CCK2 receptor antagonist CR2945 inhibited the expression of this behavior, a panicolytic-like effect. Therefore, the elevated T-maze, in contrast to other animal models of anxiety, can detect the anxiety-eliciting effects of CCK-8s both after its systemic and central administration. Also, the results provide further evidence about the involvement of a CCK-mediated mechanism within the DPAG in the regulation of panic-related defensive behaviors. © 2004 Elsevier Inc. All rights reserved. Keywords: Dorsal periaqueductal gray; Cholecystokinin; Panic; Anxiety; Elevated T-maze 1. Introduction Over the last 20 years several studies have indicated that the neuropeptide cholecystokinin (CCK) is involved in the neurobiology of anxiety, particularly in panic disorder [4,6,8,18,22,25,33]. CCK is the most widespread peptide sys- tem in the brain and exists in several forms such as CCK-7, CCK-5, CCK-8, CCK-22 and CCK-33 [10]. The sulfated form of CCK-8 (CCK-8s) is the predominant fragment of ∗ Corresponding author. Tel.: +55 16 602 3353; fax: +55 16 633 2301. E-mail address: zangross@fmrp.usp.br (H. Zangrossi Jr.). CCK in the central nervous system where it acts as an ago- nist at both subtypes of CCK receptors, CCK1 and CCK2. CCK-4, on the other hand, is a full agonist of CCK2 receptors [22]. Administration of CCK-4 induces panic attacks in healthy volunteers and in patients with panic disorder [4,5,7,33]. This fragment also causes anxiogenic effects in rodents submit- ted to different models of anxiety such as the elevated plus- maze, the light dark-transition and the ultrasonic vocalization tests [35,36]. However, systemic administration of CCK-8s has failed to consistently change anxiety-related behaviors [1,10,24,36]. 0196-9781/$ – see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.peptides.2004.06.016