Significant increase in the aggressive behavior of transgenic mice overexpressing peripheral progastrin peptides: Associated changes in CCK ₂ and serotonin receptors in the CNS

The gastrin precursor peptide, progastrin (PG), is secreted from enteroendocrine cells in the intestine and increased in patients with hypergastrinemia and colorectal cancers. In recent years, we and others have demonstrated an important role of PG peptides in colorectal carcinogenesis, and were surprised to note significant changes in the behaviors of transgenic mice overexpressing PGs. In the present studies, we examined emotional behaviors of transgenic mice overexpressing PG in the intestinal and peripheral circulation. Aggression, locomotor activity and anxiety-like behaviors of the homozygous transgenic (Tg/Tg) mice and the wild-type (WT) littermates were examined by intruder/resident test, open field and elevated plus maze, respectively. A significant increase in the aggression, locomotor activity, and anxiety-like behaviors was detected in the Tg/Tg vs WT mice. As CCK, CCK₂ receptors (CCK₂R), and 5-HT_1A receptors (5-HT _1AR) in the CNS play an important role in these behaviors, possible changes in the expression of CCK and CCK₂R and the density of CCK₂R and 5-HT_1AR were determined by either real-time RT-PCR or autoradiography of ligand binding assays. The results suggest that the expressions of CCK and CCK₂R were increased in the hypothalamus, and the density of CCK₂R were increased in the hypothalamus and amygdala of Tg/Tg vs WT mice. Similarly, the density of 5-HT_1AR was increased in the hypothalamus. Our results suggest that an upregulation of the CCK response system and 5-HT_1AR in the hypothalamus of Tg/Tg mice may mediate the alterations in the observed behaviors of these mice.