Cholecystokinin (CCK) is one of a number of hormones that play important roles in the digestive process, but that have also been found in the brain where they function as neurotransmitters (chemical messengers that carry messages between nerve cells). There are two known receptors through which cholecystokinin produces its effects. These have been labeled the CCK-A and CCK-B receptors. Animal work suggests that the CCK-B receptor may play a role in the experience of anxiety or fear; and some human work suggests it may be important in one type of anxiety disorder, called Panic Disorder. Drugs that block the CCK-B receptor may be able to reduce anxiety. The CCK-B receptor has not been well studied in humans, due to a lack of research tools. Pentagastrin has been commercially available for many years in this country, originally developed as a synthetic version of gastrin, another digestive hormone, and used to test humans for acid secreting capacity. Pentagastrin is also a very strong activator of the CCK-B receptor and can be used to explore its functions. Work with pentagastrin has suggested that CCK-B receptors may play a role in regulating activity in the human hypothalamic-pituitary-adrenal (HPA) axis, which is a central stress response system in the body. The goals of this project are to: (1) develop pentagastrin as a tool to study CCK-B receptor function in humans; (2) determine whether CCK plays a physiological role in regulating the human HPA axis and explore mechanisms; and (3) develop pentagastrin as a laboratory model to study Panic Disorder. A series of experiments will examine basic aspects of CCK-B effects on the HPA axis in detail, using over 100 healthy subjects. One small experiment will test differences between patients with Panic Disorder and healthy control subjects in emotional, physical, and hormonal responses to pentagastrin. This will help determine whether patients with Panic Disorder have an abnormality in CCK-B receptor sensitivity. All of these studies will center on pentagastrin+s effects on adrenocorticotropin (ACTH) and cortisol, two critical stress response hormones.
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