Bombesin Receptors as a Novel Anti-Anxiety Therapeutic Target: BB₁Receptor Actions on Anxiety through Alterations of Serotonin Activity

Abstract

The effects of PD 176252 [3-(1H-indol-3-yl)-N-[1-(5-methoxy-pyridin-2-yl)-cyclohexylmethyl]-2-methyl-2-[3-(nitro-phenyl)ureido]propionamide], a nonpeptide bombesin (BB) BB 1 /BB 2 receptor antagonist, were assessed in rats using several ethologically relevant tests of anxiety. Consistent with a role for the bombesin family of peptides in subserving anxiety behaviors, the antagonist increased social interaction

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

“…Studies comparing the potencies of NMB to GRP as well as binding studies or antagonist studies provide evidence that the BB 1 receptor can stimulate contraction of urogenital and gastrointestinal smooth muscle (esophageal, gastric, colon, and gallbladder) (Regoli et al, 1988;von Schrenck et al, 1989von Schrenck et al, , 1990Severi et al, 1991;Kilgore et al, 1993;Parkman et al, 1994;Milusheva et al, 1998), potently inhibit thyrotropin release from the pituitary gland by acting as an autocrine and paracrine regulator (Rettori et al, 1992;Pazos-Moura et al, 1996;Ortiga-Carvalho et al, 2003), and have potent CNS effects including inhibiting food intake independent of BB 2 stimulation (Ladenheim et al, 1994(Ladenheim et al, , 1996b(Ladenheim et al, , 1997bMerali et al, 1999;Ladenheim and Knipp, 2007) and mediating aspects of the stress and fear responses as well as various behaviors such as spontaneous activity (Merali et al, 2002(Merali et al, , 2006. BB 1 receptor knockout mice are now available and have undergone a limited number of investigations for actions of NMB Oeffner et al, 2000;Yamada et al, 2002bYamada et al, , 2003Yamano et al, 2002) (Table 1).…”

“…In BB 1 receptor knockout mice dysregulation of the thyroid occurred, suggesting that BB 1 receptor pathways are significantly involved in both TSH gene regulation and function (Oliveira et al, 2006), dysfunction in response to stress was seen (Yamada et al, 2002b;Yamano et al, 2002), impairment in the modulation of the CNS 5-HT system in response to stress occurred (Yamano et al, 2002), and an impairment of learning and memory was seen . The alterations in the CNS 5-HT and stress in these animals is particularly interesting, because the dorsal raphe nucleus is one of the brain regions that has a preponderance of BB 1 receptors (Wada et al, 1990;Ladenheim et al, 1992;Pinnock et al, 1994;Merali et al, 2006), which are located on 5-HT neurons, and stimulation of this nucleus by NMB stimulates release of 5-HT, resulting in anxiogenesis (Merali et al, 2006). In a study in rats using BB 1 and BB 2 receptor agonists and antagonists (Bédard et al, 2007), data were provided to show that both GRP and NMB affect the stress response.…”

“…GRP stimulates smooth muscle contraction in both the gastrointestinal tract and urogenital system and has profound effects on GI motility, stimulates release of numerous gastrointestinal hormones/neurotransmitters, stimulates secretion and/or hormone release from the pancreas, stomach, colon, and numerous endocrine organs, has potent effects on immune cells (macrophages, dendritic cells, lymphocytes, and leukocytes) (Ruff et al, 1985;De la Fuente et al, 1991van Tol et al, 1993;Plaisanci é et al, 1998;Makarenkova et al, 2003), has potent growth effects on both normal tissues and tumors; has potent CNS effects, including regulation of circadian rhythm, thermoregulation; regulation of anxiety and the fear response, regulation of food intake, and behavioral effects and is involved in mediating numerous CNS effects on the GI tract (Tache et al, 1988;Bunnett, 1994;Martinez and Tache, 2000;Jensen et al, 2001;Jensen, 2003;Grider, 2004;Jensen and Moody, 2006). In many tissues the effects of NMB overlap with those of GRP; however, NMB has specific effects in some tissues such as contraction of smooth muscle, growth effects in various tissues (Moody et al, 2000;Matusiak et al, 2005), CNS effects including effects on feeding, thermoregulation; regulation of TSH release, stimulation of various CNS neurons, behavioral effects; and effects on spinal sensory transmission (von Schrenck et al, 1989;Rettori et al, 1992;Ladenheim et al, 1997b;Ohki-Hamazaki, 2000;Merali et al, 2006;Oliveira et al, 2006). GRP and to a lesser extent NMB affects the growth and/or differentiation of a number of important human tumors including colon, prostate, lung, and some gynecologic cancers Schally et al, 2000;Jensen et al, 2001;Glover et al, 2003;Jensen and Moody, 2006).…”

Gut feelings about depression

“…Yet another link between eating and depressive disorders and comorbid anxiety has come from the findings that pharmacological treatments to reduce anxiety (e.g., benzodiazepines) have the propensity to increase eating and that agents that reduce eating (e.g., neuromedin B, gastrin-releasing peptide, corticotropin-releasing hormone) promote anxiety. 3 In light of such findings, there has been interest in determining whether key hormones associated with eating processes might also contribute to anxiety and depressive disorders and potentially serve as targets in the treatments of depression or as potential biomarkers for illness subtypes. 4 We suggest that several hormones act additively or interactively in determining eating responses to stressors as well as depressive mood and that these hormones, or the genes associated with them, can serve as biomarkers and potential therapeutic targets in the treatment of depressive disorders.…”

“…By example, other hormones that affect eating and energy regulation, including bombesin and glucagon-like peptide-1 (GLP-1), the latter also affecting glucose regulation in type 2 diabetes, have also been implicated in mood disorders. 3,26 At the moment, the causal link between depressive disorders and obesity, and the peptides associated with energy balance, is still uncertain, as they could be etiologically involved in depressive disorders or simply be markers of illness. Ultimately, prospective studies assessing specific attributes of the depressive and metabolic profiles will be needed to clarify the nature of the associations.…”