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24 Cholecystokinin Peptides in Brain Function

Cholecystokinin (CCK) is a peptide originally discovered in the gastrointestinal tract but is also found in high density in the mammalian brain. The C‐terminal sulfated octapeptide fragment of CCK8 constitutes one of the major neuropeptides in the brain. CCK8, interacting with nanomolar affinities with two different receptors designated CCK1 and CCK2, has been shown to be involved in numerous physiological functions and is involved in the modulation and control of multiple central functions. In particular, CCK is involved in the neurobiology of anxiety, depression, psychosis, cognition, nociception, and feeding behavior. The functional role of CCK has been facilitated thanks to the development of potent and selective CCK receptor antagonists and agonists. In this chapter, the strategies followed to design these probes, and their use to study the anatomy of CCK pathways, the neurochemical and pharmacological properties of this peptide, and the clinical perspectives offered by manipulation of the CCK system are reported. List of Abbreviations: ACC, anterior cingulate cortex; APA, aminopeptidase A; CCK, cholecystokinin; CCKLM, CCK‐like material; CNS, central nervous system; GABA, gamma‐aminobutyric acid; GPCR, G‐protein‐coupled receptor; IP3, inositol 1,4,5‐triphosphate; JNK, c‐Jun‐NH2‐terminal kinases; LETO, Long–Evans Tokushima Otsuka; MAPK, mitogen‐activated protein kinase; NTS, nucleus tractus solitarius; OLETF, Otsuka Long–Evans Tokushima fatty; PC, prohormone convertase; PKA, protein kinase A; PKC, protein kinase C; PLA2, phospholipase A2; PLC, phospholipase C; PTX, pertussis toxin; TM, transmembrane‐spanning domains; VTA, ventral tegmental area