Role of bombesin (BN)-like peptides/receptors in emotional behavior by comparison of three strains of BN-like peptide receptor knockout mice

Abstract

Keywords: gastrin-releasing peptide receptor (GRP-R); bombesin receptor subtype-3 (BRS-3); neuromedin B receptor (NMB-R); light-dark (L-D) box test; elevated plus maze test; anxiety; emotion; knockout mice Bombesin (BN)-like peptides are involved in the regulation of a wide variety of behaviors, such as spontaneous activity and feeding. We assessed the role of BN-like peptides/receptors in emotional and/or anxietyrelated behavior using three strains of knockout mice, each deficient in a single BN-like peptide receptor (gastrin-releasing peptide receptor, bombesin receptor subtype-3, or neuromedin B receptor). Two representative behavioral paradigms, the light-dark (L-D) box test and the elevated plus maze test, were chosen for this purpose. In these two tests, the level of anxiety can be measured as the preference for exploring the light box, or the length of time spent in the open arms, respectively. By conventional parameters, the only significant finding was that BRS-3-deficient mice exhibited a longer duration of remaining in the open arms compared to the wild-type cohort (P Ͻ 0.01). However, analyses of risk assessment behavior revealed that BRS-3-deficient mice exhibited increased 'stretched attend posture' behavior (P Ͻ 0.01, compared to wild-type mice in both the L-D box and elevated plus maze tests) while NMB-Rdeficient mice exhibited decreased behavior (P Ͻ 0.05, compared to wild-type mice in both tests). These results suggest that BN-like peptides/receptors may play a role in modulating emotion including some forms of anxiety (eg, risk assessment behavior). Further, we found that the type of emotional behavior to which each of the peptide/receptor pathways contributes can be clearly specified. Molecular Psychiatry (2002) 7, 113-117. DOI: 10.1038/ sj/mp/4000974 Bombesin (BN) was originally purified from the skin of the European frog (Bombina bombina), 1 while the BNlike peptides gastrin-releasing peptide (GRP) and neuromedin B (NMB) were purified from mammalian tissues.2,3 These peptides exert their effects by binding to G-protein coupled receptors such as the GRP receptor (GRP-R), the NMB receptor (NMB-R), and the BN receptor subtype-3 (BRS-3) for which no specific endogenous ligand(s) has yet been identified. 4,5 BN-like peptides and their receptors are widely distributed in the mammalian CNS and modulate many aspects of behavior such as spontaneous activity and feeding behavior, as well as learning and memory. 6-9 We previously produced three strains of BN-like peptide receptor knockout mice using a gene targeting strategy. The resulting GRP-R-, NMB-R-and BRS-3-deficient mice were used in studies designed to clarify and distinguish the functional properties of BN-like peptides. These knockout mice exhibit unique phenotypes, such as elevated spontaneous activity and non-aggressive social behaviors in GRP-R-deficient mice.10-12 BRS-3-deficient mice exhibit moderate hyperphagia and obesity, 13 altered taste-related behaviors, 14 and decreased social behavior. 15 However, no behavioral phenotype has yet...

Facilitation of the Inhibitory Transmission by Gastrin-Releasing Peptide in the Anterior Cingulate Cortex

“…A balance between excitatory and inhibitory transmission is critical for many brain functions. Previous reports show that the GRP in the amygdala is inovolved in behavioral fear [18,31-36]. In addition to the amygdala, recent studies show that lesion of the ACC produced an impairment in trace fear conditioning [37] and electrical stimulation of the ACC induced fear memory [38].…”

International Union of Pharmacology. LXVIII. Mammalian Bombesin Receptors: Nomenclature, Distribution, Pharmacology, Signaling, and Functions in Normal and Disease States

“…Furthermore, the levels of the MCH receptor and prepro-MCH mRNAs in the hypothalamus of BB 3 receptor knockout mice were higher than those of controls, suggesting that up-regulation of the MCH receptor and MCH occurs in the knockout mice, which triggers hyperphagia and probably upsets the mechanism by which leptins decrease MCH receptors and feeding (Maekawa et al, 2004). Studies of BB 3 receptor knockout mice suggest that this receptor is important in various behavioral effects, including the neural mechanisms that regulate social isolation (Yamada et al, 2000a), and are important in modulating emotion including forms of anxiety (Yamada et al, 2002a).…”

Pharmacology of putative selective hBRS-3 receptor agonists for human bombesin receptors (BnR): Affinities, potencies and selectivity in multiple native and BnR transfected cells

“…More recent studies demonstrate BRS-3 receptors are present on pancreatic islets [8] and BRS-3 knockout animals have altered plasma insulin levels and altered glucose transporter 4 function [28,30]. Furthermore, from target receptor deletion (knockout) and expression studies, it has been reported that the BRS-3-receptor is frequently over-expressed by various tumors [7,18,34,40], its presence plays a role in tumor invasiveness [13,15,18,57], a role in lung development, bronchial epithelial cell proliferation and lung injury [15,41–43,53], a role in taste preference [63], social response/anxiety [61,62], and may play an important role in regulating gastrointestinal motility [32]. …”