The role of gastrin and cholecystokinin in normal and neoplastic gastrointestinal growth

Gastrin is transiently expressed in fetal islets during a critical period of their development from protodifferentiated islet precursors in fetal pancreatic ducts. To examine the possible role of gastrin as an islet cell growth factor, postnatal islet growth was studied in transgenic mice which overexpress gastrin and TGF alpha in their pancreas. Overexpression of a TGF alpha transgene causes metaplastic ductules containing numerous insulin expressing cells that resemble protodifferentiated precursors of the fetal pancreas. However, islet mass of the TGF alpha transgenic mice was not increased. Pancreatic overexpression of gastrin from a chimeric insulin/gastrin transgene transcribed from the insulin promoter markedly decreased the TGF alpha-stimulated increase in pancreatic duct mass. Furthermore, pancreatic coexpression of both gastrin and TGF alpha significantly increased islet mass in mice expressing both transgenes. These findings indicate that TGF alpha and gastrin can act synergistically to stimulate islet growth, although neither peptide alone is sufficient. Islet growth may possibly be stimulated through gastrin promoting the differentiation of insulin-positive cells in the TGF alpha-induced metaplastic ducts. This transgenic study suggests that islet neogenesis can be reactivated in the ductular epithelium of the adult pancreas by local expression of two growth factors, gastrin and TGF alpha.

PD134308 and PD135158 are potent and selective antagonists at the cholecystokinin type B (CCK-B) receptors with IC50 values of 1.6 nM and 3.5 nM, respectively, in the radioligand binding assay and Ke values of 7.82 and 12.9 nM, respectively, in their blocking action on CCK responses in the rat lateral hypothalamic slice. PD134308 and PD135158 produced potent anxiolytic effects in the mouse black/white box test after either subcutaneous or oral administration. There was no evidence of the development of tolerance to the anxiolytic action of either PD134308 or PD135158 in mice treated twice daily for 7 days, nor was there any sign of withdrawal anxiogenesis after abrupt termination of this treatment. Both CCK-B antagonists were able to suppress the withdrawal anxiogenesis and produce an anxiolytic effect in mice previously made tolerant to diazepam. PD134308 and PD135158 produced potent anxiolytic effects in the rat elevated plus maze test and the rat social interaction test. The effects were comparable in magnitude to those seen with diazepam. However, unlike diazepam, PD134308 and PD135158 did not produce sedation. The CCK-B antagonists also showed powerful anxiolytic activity in the "marmoset human threat test." These results provide evidence of a selective role for CCK-B receptors in the control of anxiety. PD134308 and PD135158 are members of a class of anxiolytic agents that have a greatly improved profile compared with benzodiazepines or serotonin-related anxiolytics.