Research reportPharmaco-ontogeny of bombesin's suppression of food intake and its attenuation by histamine H3 receptor agonists
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.
Section snippets
Subjects
Male Sprague–Dawley rat pups (Charles River, St. Constant, Quebec), bred and reared locally in the laboratory colony, were used. On the day of birth (PD 0), litters were standardized to groups of 8–12 pups per dam with each litter counterbalanced for sex. Until the day of testing (PD 1, 5, 10 and 15) pups were kept with the dam. The colony room was temperature-regulated (20°C) with a relative humidity of 60% and maintained on a 12 h light–dark cycle with lights on at 07.00 h.
Experimental procedure
Prior to testing,
Results
The analyses revealed that BN doses significantly affected milk intake (F1, 158=27.86; P<0.0000), as did the age of peptide exposure (F3, 158=19.89; P<0.0000). Tukey's multiple comparisons of the means comprising these effects confirmed that the milk intake varied with BN dose, in that at higher doses (0.06 and 0.6 mg/kg) BN-elicited suppression of food intake was greater than that noted at the lower dose (0.006 mg/kg). This pattern was very similar across all ages tested. However, at PD 15, BN
Discussion
A number of conclusions can be drawn from the results of the present study. First, administration of BN suppressed food intake in neonatal rats from PD 1 through PD 15. These results are concordant with recent findings in our laboratory that show that rats are responsive to the feeding suppressant effects of BN early in ontogeny [12]. These findings further suggest that BN/GRP receptors are functional and may play a critical role in feeding regulation very early in development. Second, when
Acknowledgements
This research was supported by a grant from the Medical Research Council of Canada to Z.M. and studentship to P.K.
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