Cholecystokinin (CCK) is the most abundant peptide neurotransmitter in the brain and its known distribution, interactions, and functions make it of great interest to psychiatry, but it has been little studied in humans. CCK may play a pathophysiological role in panic disorder--which is a common, disabling disorder with high social morbidity costs. It may also play a role in modulating the hypothalamic-pituitary-adrenal (HPA) axis-- which appears dysregulated in panic, as well as depression and other psychiatric disorders. Agonists of a central CCK receptor (CCK-B) induce panic attacks and activate the HPA axis, but mediating mechanisms have not been identified. The goals of this project are: (l) to further develop the CCK-B agonist pentagastrin as a neuroendocrine probe for studying CCK-B receptor function in humans; (2) to determine whether CCK plays a physiological role in the regulation of the human HPA axis and explore mediating mechanisms; (3) to further develop pentagastrin as a laboratory model of panic disorder and explore its mechanisms of angiogenesis. Five experiments are planned. The first will determine the dose-response curves for HPA activation and subjective symptoms in response to intravenous pentagastrin. The second will examine HPA responses to pentagastrin at different times of day and different levels of basal glucocorticoid activity. The third will test the ability of a selective CCK-B antagonist (CI-988) to block HPA and symptom responses to pentagastrin. The fourth will use metyrapone pre-treatment to examine the effect of reduced cortisol levels on the HPA response to pentagastrin. The fifth will compare panic patients to controls in symptom and HPA responses to pentagastrin and determine whether a cognitive intervention that should reduce the intensity of symptom responses will also reduce the HPA response. Additional experiments will examine adrenergic or GABAergic blockade of pentagastrin effects. If the HPA response to pentagastrin is dose-dependent and independent of symptoms, this will suggest that CCK plays a physiological role in modulating the human HPA axis. If the HPA response is independent of cortisol feedback inhibition, this will differentiate CCK from other stress axis modulators and enhance its value as a new probe for studying HPA axis regulation. If cognitive intervention blocks pentagastrin-induced panic in patients, but the HPA response remains robust and normal, this will contradict the hypothesis that altered CCK-B receptor sensitivity plays a role in the reported panicogenic activity of CCK-B agonists. These studies will build the foundation needed to develop pentagastrin into a widely useful tool for studying neuroendocrine regulatory mechanisms, human CCK-B receptor function, and the pathophysiology of anxiety and affective disorders.
