Cholecystokinin and Panic Disorder: Reflections on the History and Some Unsolved Questions.

Jens F Rehfeld

doi:10.3390/molecules26185657

Abstract

The classic gut hormone cholecystokinin (CCK) and its CCK2-receptor are expressed in almost all regions of the brain. This widespread expression makes CCK by far the most abundant peptidergic transmitter system in the brain. This CNS-ubiquity has, however, complicated the delineation of the roles of CCK peptides in normal brain functions and neuropsychiatric diseases. Nevertheless, the common panic disorder disease is apparently associated with CCK in the brain. Thus, the C-terminal tetrapeptide fragment of CCK (CCK-4) induces, by intravenous administration in a dose-related manner, panic attacks that are similar to the endogenous attacks in panic disorder patients. This review describes the history behind the discovery of the panicogenic effect of CCK-4. Subsequently, the review discusses three unsettled questions about the involvement of cerebral CCK in the pathogenesis of anxiety and panic disorder, including therapeutic attempts with CCK2-receptor antagonists.

Highlights

Cholecystokinin (CCK) is an established gut hormone that stimulates gallbladder contraction and the emptying of bile into the small intestine [1], its name
Since panic disorder is a rather common psychiatric condition, with a prevalence among women of 5% and 2% in men [21], you could argue that some involvement of the cerebral CCK-system in the pathogenesis of panic attacks should not come as a surprise
It was unexpected that a simple intravenous bolus injection of the C-terminal tetrapeptide fragment of CCK should open the gates for decades of comprehensive studies of the role of CCK in panic disorder

Summary

Introduction

Cholecystokinin (CCK) is an established gut hormone that stimulates gallbladder contraction and the emptying of bile into the small intestine [1], its name. The discovery that the activity of gastrin could be mimicked by the smaller C-terminal tetrapeptide fragment in the 1960s [34] had two immediate consequences: First, the tetrapeptide was a considerably cheaper secretagogue to synthetize in comparison with the full-length gastrin-17 peptide, and gastrin was needed for clinical and basic studies of gastric acid secretion The context in those years was that gastrin and its effect on acid secretion was essential for understanding the pathophysiology of the widespread duodenal ulcer disease. A useful gastrin-4 based drug never materialized, and some pharmaceutical companies had stocks of unused synthetic tetragastrin (alias CCK-4) One of these companies was the Danish LEO Pharmaceutical Products, who had prepared thousands of ampoules, each containing 70 μg of the tetrapeptide, to be injected as a bolus in dyspeptic ulcer patients for measurement of the gastric acid output. The effect on growth hormone secretion was small, but the “side” effect was dramatic

The Panicogenic Activity of CCK-4

Does the Brain Synthesize CCK-4 as a Separate Neuropeptide?

Is Endogenous CCK in Plasma Associated with Panic Disorder?

Conclusions