Cholecystokinin Signaling in Anxiety Disorders

Cholecystokinin (CCK) has long been recognised as a digestive hormone; over the past decades it has emerged as one of the most abundant neuropeptides in the central nervous system. Two principal receptor subtypes, CCK1R and CCK2R, mediate its diverse actions. In the periphery, CCK modulates pancreatic secretion and gallbladder contraction, whereas in the CNS it functions as a neuromodulator within limbic circuits, notably the amygdala and hippocampus. Experimental administration of CCK-4, a tetrapeptide fragment, reliably induces panic attacks in susceptible individuals, implicating CCK2R signalling in the pathogenesis of panic disorder and other anxiety states. Preclinical studies in rodents have linked CCK signalling to alterations in GABAergic and glutamatergic transmission, stress responsiveness and hypothalamic–pituitary–adrenal axis activation. Emerging evidence suggests that aberrant CCK2R activation may amplify fear conditioning and hypervigilance through potentiation of synaptic plasticity in key anxiety-related networks. Therapeutic efforts have focused on developing selective CCK2R antagonists, with promising preclinical modulation of panic symptoms, although translation to clinical practice remains in early phases. Better understanding of CCK’s interplay with classical neurotransmitter systems offers the prospect of novel treatments for anxiety disorders with improved efficacy and tolerability.

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Cholecystokinin Signaling in Anxiety Disorders publication trend

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Technical terms

Cholecystokinin (CCK): A peptide hormone and neurotransmitter that modulates digestive processes and central nervous system activity, implicated in anxiety regulation.

CCK2 receptor (CCK2R): A G-protein coupled receptor subtype predominantly expressed in the brain, mediating CCK-induced panicogenic effects.

Agonist: A compound that binds to a receptor to activate a biological response.

Antagonist: A molecule that binds to a receptor without activating it, thereby blocking the action of agonists.

Panicogenic: Capable of inducing panic or intense fear.

Amygdala: A limbic brain structure critical for the processing of fear and anxiety-related responses.

References

1. Bromophenols from Symphyocladia latiuscula (Harvey) Yamada as Novel Cholecystokinin 2 Receptor Antagonists. Journal of Integrative Neuroscience (2023).
2. Cholecystokinin and Panic Disorder: Reflections on the History and Some Unsolved Questions. Molecules (2021).
3. Cholecystokinin—From Local Gut Hormone to Ubiquitous Messenger. Frontiers in Endocrinology (2017).
4. On the Role of Cholecystokinin (CCK) in Fear and Anxiety: A Review and Research Proposal. Journal of Human Psychology (2019).