Altered Emotional Behaviors in Mammalian Bombesin Receptor Knockout Mice: Implication for the Molecular Pathogenesis of Stress-Induced Psychiatric Disorders in Humans

Neuropeptides are thought to play important roles in the pathogenesis of various psychiatric disorders, including posttraumatic stress disorder (PTSD) (Merali et al. 2002). To elucidate the pathophysiological role of neuropeptides for the disorders in vivo, we have employed behavioral analyses of gene-manipulated mice lacking their receptors. Among various neuropeptides, we have focused on bombesin, because its receptors are highly expressed in the hippocampus and the amygdala. Both regions are known to mediate memory and emotional behaviors. Bombesin (BN) is a tetradecapeptide originally purified from the skin of the European frog Bombina bombina (Anastasi et al. 1971). Two BN-like peptides, gastrin-releasing peptide (GRP) and neuromedin B (NMB), have been identified in mammalian tissues (McDonald et al. 1979; Minamino et al. 1983). These peptides exert their effects by binding to G-protein coupled receptors on the cell surface; these are the GRP-preferring receptor (GRP-R) and the NMB-preferring receptor (NMB-R). In addition, a third subtype of mammalian bombesin receptor (BRS-3) has been cloned; however, high affinity natural ligand(s) specific to BRS-3 have not yet been identified (Battey and Wada 1991; Fathi et al. 1993). BN-like peptides and their receptors are widely distributed in the mammalian central nervous system and modulate many aspects of behavior such as spontaneous activity and feeding behavior, as well as learning and memory (Flood and Morley 1988; Flynn 1991; Kirkham et al. 1993; Santo-Yamada et al. 2001). We previously produced three strains of BN-like peptide receptor knockout mice using a gene-targeting method (Ohki-