Sustained bombesin exposure results in receptor down-regulation and tolerance to the chronic but not acute effects of bombesin on ingestion

Acute intracerebroventricular (i.c.v.) administration of bombesin (BN) reduces meal intake in fasted rats. The overall objective of the present study was to determine the behavioral and other ingestive effects of prolonged central administration of BN. In the first experiment, we characterized the effects of 8-day sustained central administration of BN (0, 0.01, 0.05, 0.1 and 5 μg/0.5 μl/h) or its antagonist (BIM-26226; 0, 0.005, 0.05, 0.5 and 5.0 μg/0.5 μl/h), in free feeding rats. Each dose was delivered over 48 h, in an ascending sequence. At the higher doses, the BN- exposed rats consumed significantly less food whereas those exposed to the BN antagonist ingested significantly more food than the controls (saline exposed), during the dark phase. Due to the limited 48-h exposure to these higher doses, we further investigated the effects of more sustained BN exposure. Thus BN was infused over a 7-day period, at a rate of 0.25 μg BN/0.5 μl/h. In this latter study, we determined the effects of sustained BN exposure on a) daily spontaneous ingestive pattern, b) the rat\u27s ingestive and other behavioral responses to a subsequent acute BN (i.c.v.) challenge and, c) BN receptor binding profile in various brain regions. Over the initial 2 days of chronic infusion, BN significantly suppressed spontaneous ingestion, and this effect dissipated by 72 h. Upon acute challenge with bolus injection of BN (0.25 μg; i.c.v.), both chronically BN-treated and control rats responded by decreased feeding and enhanced grooming behaviors. In terms of effects at the receptor level, chronic BN exposure resulted in significant down-regulation (reduced BN/GRP receptor density) at the PVN and the hippocampal dentate gyms. These findings represent the first demonstration of concomitant behavioral and receptor based changes consequent to sustained exposure to BN. These data suggest that tolerance to feeding suppressant effects of BN develops gradually, which in part may be mediated by down-regulation of BN/GRP receptors at specific brain loci. Our results also suggest that despite the development of tolerance to the chronic or sustained effects of BN exposure, animals still respond robustly to acute fluctuations in peptide levels