Investigation of cholecystokinin system genes in panic disorder

Abstract

There is evidence for the role of the cholecystokinin (CCK) neurotransmitter system in the neurobiology of panic disorder (PD).¹ The CCK receptor agonist, CCK-tetrapeptide (CCK-4) fulfills criteria for a panicogenic agent¹ and there is evidence that PD might be associated with an abnormal function of the CCK system. For example, PD patients show an enhanced sensitivity to CCK-4, and exhibit lower CSF and lymphocyte CCK concentration as compared to healthy controls (reviewed by Bradwejn et al.²). Also, untreated PD patients display an increased CCK-4-induced intracellular Ca²⁺ mobilization in T cells relative to treated PD, depression and schizophrenia.³ The CCK receptors have been classified into two subtypes: CCK-A and CCK-B. We report here a study of polymorphisms in the CCK pre-pro hormone gene (CCK), CCK-AR, and CCK-BR in DSM-IV panic patients (n = 99) vs controls matched for gender and ethnicity. The CCK polymorphism revealed no association with PD. We identified a new polymorphism for the CCK-A receptor gene, and tested it in our sample, with negative results. A single nucleotide polymorphism has been found in the coding region of the CCK-B receptor gene⁴ (CCK-BR) and D Collier (personal communication) identified a highly polymorphic dinucleotide (CT)_n microsatellite in the 5′ regulatory region. For the CCK-B receptor gene polymorphism, PD patients showed a significant association. Our genetic dissection of the CCK system thus far suggests that the CCK-B receptor gene variation may contribute to the neurobiology of panic disorder.