Cholecystokinin (CCK) is a quintessential neuropeptide. Long known as one of the gastrointestinal pancreozymin hormones, cholecystokinin is released from the gastric mucosa when food enters the intestinal tract. Circulating CCK stimulates the pancreas to release digestive amylase and the gall bladder to contract. In 1973, Gerry Smith and coworkers at Cornell discovered that released CCK acts as a satiety signal, initiating neural feedback through the vagus nerve to brain regions mediating ingestion, one of the first demonstrations of a behavioral action of a peripheral neuropeptide. Advances in radioimmunoassay and immunocytochemistry yielded exciting news of CCK in the brain. At the Karolinska Institute in 1980, Tomas Hökfelt and coworkers made the iconoclastic discovery that CCK coexists with dopamine in mesolimbic neurons projecting to the nucleus accumbens. The concept of coexisting neuropeptides modulating the actions of classical neurotransmitters was elaborated in functional studies, including the modulatory actions of CCK on neuronal firing rates, neurotransmitter release, signal transduction, neural injury, nociception, exploratory activity, and rewarded behaviors. Two subtypes of CCK receptor were cloned: CCK-A (for alimentary, later changed to CCK-1) primarily localized in the periphery, and CCK-B (for brain, now CCK-2) distributed in the central nervous system. Several major pharmaceutical companies embarked on the search for cholecystokinin receptor antagonists with therapeutic potential. Some of the first non-peptide subtype-selective ligands for neuropeptide receptors were generated by Merck for the CCK receptor subtypes. Clinical studies with CCK ligands explored indications including schizophrenia, appetite suppression, anorexia, emesis, analgesia, anxiety, and panic disorder.

As a behavioral neuroscientist working on neurotransmitters regulating behaviors relevant to psychiatric disorders, I became intrigued by the burgeoning number of new peptide neurotransmitters, their coexistences, and their apparent functional roles as neuromodulators. It made evolutionary sense that neural networks were composed of major excitatory and inhibitory circuits, with modulatory overlays designed to push gently or dramatically as the situation demanded. We worked out the role of CCK in mesolimbic behaviors in rats. Our laboratory contributed the first findings that cholecystokinin had no effect alone but modulated dopamine-mediated behaviors when microinjected into the nucleus accumbens. It was quite a complicated story. CCK potentiated dopamine release and dopamine-mediated hyperlocomotion via a CCK-1 receptor in the shell of the accumbens, while CCK inhibited dopamine release and dopamine-mediated hyperlocomotion via a CCK-2 receptor in the core of the accumbens.

Jean-Jacques Vanderhaeghen and I organized the first international conference on neuronal CCK in Brussels in 1984. The CCK research field grew exponentially thereafter, with a steady stream of publications, conferences, and books documenting the expanding literature. Rebecca Corwin joined our laboratory as a postdoctoral fellow to pursue the modulatory action of CCK on dopamine release using the recently developed in vivo microdialysis technology. We accepted an invitation from Abba Kastin, editor of the journal Peptides, to compile a comprehensive review of the CCK literature. Our 1994 review summarized the extensive literature on CCK synthesis, metabolism, gene expression, neuroanatomy, coexistences, receptors, ligands, and their actions on neurophysiology, release, digestion, satiety, cardiovascular regulation, respiration, thermoregulation, sexual behaviors, sleep, seizures, pain, lung cancer, self-stimulation, drug abuse, exploratory hyperlocomotion, memory, anxiety, panic, and schizophrenia. Citation Classic status conferred by the Institute for Scientific Information on this review article attests to the ongoing prominence of basic and clinical research into the biological importance of CCK.