Cholecystokinin (CCK) is the most abundant neuropeptide in the human brain. In animals, centrally administered CCK agonists are anxiogenic in a variety of animal models of anxiety. In humans, peripherally administered CCK agonists lead to anxiety and panic, and the anxiogenic effects of CCK are significantly greater in patients with panic disorder. In animals, treatment with 5-HT3 antagonists prevent the anxiogenic effects of CCK, and have been demonstrated in microdialysis studies to prevent 5-HT-induced CCK release in cortical tissue. Interestingly, 5- HT3 antagonists have been reported to be therapeutic in patients with social phobia and panic. Studies conducted within the Unit on Anxiety have demonstrated that the effects of pentagastrin, a CCK agonist, are dose-related in healthy volunteers. Further, like patients with panic disorder, patients with social phobia are more sensitive to the anxiogenic effects of pentagastrin than healthy controls. Acute administration of intravenous ondansetron, a 5-HT3 antagonist, has been found ineffective in blocking the anxiogenic effects of pentagastrin in patients with anxiety disorders. Ongoing studies are investigating the effects of chronic oral treatment with ondansetron on pentagastrin- induced anxiety and panic.