Significant Increase in the Aggressive Behavior of Transgenic Mice Overexpressing Peripheral Progastrin Peptides: Associated Changes in CCK2 and Serotonin Receptors in the CNS

Abstract

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, CCK 2 receptors (CCK 2 R), and 5-HT 1A receptors (5-HT 1A R) in the CNS play an important role in these behaviors, possible changes in the expression of CCK and CCK 2 R and the density of CCK 2 R and 5-HT 1A R were determined by either real-time RT-PCR or autoradiography of ligand binding assays. The results suggest that the expressions of CCK and CCK 2 R were increased in the hypothalamus, and the density of CCK 2 R were increased in the hypothalamus and amygdala of Tg/Tg vs WT mice. Similarly, the density of 5-HT 1A R was increased in the hypothalamus. Our results suggest that an upregulation of the CCK response system and 5-HT 1A R in the hypothalamus of Tg/Tg mice may mediate the alterations in the observed behaviors of these mice.

Wiring and Volume Transmission in Rat Amygdala. Implications for Fear and Anxiety

“…In agreement with the latter, the overexpression of progastrin peptides increases the density of CCK-2 receptors in the amygdala and produces an anxious phenotype as indicated in the Elevated Plus-Maze [115]. Surprisingly, the results of experiments using CCK-2 deficient mice have been rather contradictory since while in some laboratories [116,117], in line with the pharmacological and genetic data reviewed above, an anxiolytic-like phenotype has been reported using the Elevated Plus-Maze no changes in behavior [118] or even an anxious phenotype [119] have been observed in other studies using the same test.…”

Regulation of Aggression by Obesity-Linked GenesTfAP-2andTwzThrough Octopamine Signaling inDrosophila

“…CCK signaling within the brain to the cholecystokinin B receptor (CCKBR) induces hyperactivity and aggression in rodents (Bellier et al 2004;Li et al 2007). TfAP-2 overexpression in octopaminergic neurons induces the expression of Figure 7 Overexpressing Dsk makes males hyperactive.…”

The neuropeptide Drosulfakinin regulates social isolation-induced aggression inDrosophila

“…As CCK is known to regulate aggression, anxiety, and social-defeat responses in rodents (Katsouni et 116 al., 2013;Li et al, 2007;Panksepp et al, 2004;Vasar et al, 1993;Zwanzger et al, 2012), we next tested 117 specific phenotypic effects of Dsk modulation. Dsk localizes to the pars intercerebralis, parts of the 118 protocerebrum and the sub-esophageal ganglion (Nichols, 1992;Nichols and Lim, 1996;Söderberg et 119 al., 2012).…”