Pharmaco-ontogeny of bombesin's suppression of food intake and its attenuation by histamine H₃ receptor agonists

Abstract

Bombesin (BN) administration has been shown to suppress food intake across diverse species. Preliminary results have shown that BN elicits a satiety-like state from postnatal day (PD) 1, through unknown mechanism(s). We have recently shown that in adult rats, α-methyl histamine (α-MH), a selective H₃ receptor agonist that inhibits the release and synthesis of histamine, blocks the feeding suppressant effects of BN. The objective of this study was to determine if such a mechanism was operation at birth or whether it developed over time. Thus effects of histamine H₃ receptor agonists as well as BN-histamine interactions in the regulation of food intake were assessed during early development. On PD 1, 5, 10 and 15, groups of food deprived Sprague–Dawley rat pups (n=8–12) were injected with BN alone (0 (saline), 0.006, 0.06 or 0.6 mg/kg, s.c.), H₃ receptor agonists alone (α-MH or Imetit (3 or 5 mg/kg s.c.)) or the combination of BN and H₃ receptor agonists, and their ingestive behavior was monitored. Results confirmed that pups were sensitive to feeding suppressant effects of BN starting from PD 1. Imetit or α-MH either failed to affect food intake or at certain time points enhanced food intake. Pretreatment with the H₃ receptor agonists significantly attenuated the feeding suppressant effects of BN, suggesting that early in ontogeny, BN may suppress food ingestion possibly by facilitating histamine release at some relevant site(s).

Introduction

Central or systemic administration of the amphibian derived tetradecapeptide bombesin (BN) and its mammalian counterparts (gastrin-releasing peptide (GRP) or neuromedin B) induce a satiety-like state. This pharmacological response to BN-like peptides is highly conserved across diverse species ranging from mice to man 13, 29. To date, the majority of the research examining BN-induced suppression of food intake has focused on adult animals. One short study by Jackson and Kitchen [6]examined the feeding suppressant effects of BN in 15-day-old rats; however, this study did not look at any earlier time points during development. More recently, results from our laboratory have shown that BN is able to suppress food intake as early as day 1 after birth [12]. These findings suggest that BN receptors may be functional very early in development and they also bring into question whether the mechanism(s) that mediate BN-induced suppression of food intake in neonatal rats is (are) similar to those operational in adult rats, considering the differences in their ingestive patterns.

Recent studies from our laboratory have shown that in adult rats, peripheral administration of R-α-methyl-histamine (α-MH) or Imetit, two selective H₃ receptor agonists known to inhibit the release and synthesis of histamine, were able to attenuate BN-induced satiety [9]. These findings suggest that BN may mediate its satiety-like effects through the histaminergic system.

Like BN, central or systemic administration of histamine agonists have been reported to inhibit food intake in the adult rat, whereas the administration of antihistaminic drugs have been shown to increase food intake [16]. Central histamine receptors (currently identified as postsynaptic H₁, H₂, and presynaptic H₃) are believed to be involved in this regulatory process. Central administration of thioperamide, a drug which blocks presynaptic autoinhibitory H₃ receptors facilitating the release of histamine, significantly decreases food intake, whereas centrally infused H₁ receptor antagonists induce feeding [16].

In addition, there is considerable functional and anatomical overlap between BN and histamine in relation to feeding in adult rats. Direct microinjections of either BN or histamine antagonists into various brain sites have implicated common hypothalamic nuclei (such as the paraventricular nucleus (PVN) and the ventromedial nucleus (VMH)) in both BN- and histamine-induced suppression of food intake 8, 15. Moreover, it has recently been shown that endogenous levels of BN-like peptides change in the hypothalamus in relation to food intake [10]. More directly, push-pull perfusion studies have revealed that BN-like peptides are released at the PVN during satiation and satiety [22]. Similarly, a physiological role for hypothalamic neuronal histamine in the regulation of food intake has been supported by the finding that manipulation of the endogenous levels of neuronal histamine by microinfusion of α-fluoromethylhistidine (FMH), a histamine synthesis inhibitor, into the PVN induces feeding [24].

Currently, little is known about the ontogeny of histamine effects on feeding behavior. During ontogeny, H₁ receptor binding sites were detected on PD 2, increased relatively slowly until PD 9 and then rapidly to reach adult levels by PD 16. In the case of the H₃ receptors, binding sites were not detectable autoradiographically until PD 9 and only reached adult levels by PD 23 [23]. In contrast, histaminergic fibers are present at PD 1 and reach adult-like levels by PD 14, and histaminergic immunoreactivity seemed to be fully expressed by embryonic day 20 17, 30. This early development of the neural histaminergic system suggests that it may be operational very early in ontogeny. Whether the histaminergic system is involved in BN-induced suppression of food intake early in development remains to be established.

The objectives of the present study were to characterize the pharmaco-ontogeny of (a) the effects of H₃ receptor agonists on food intake, and (b) BN-histamine interactions, in the regulation of ingestive behavior.