Administration Of Bombesin Research Articles

Gastroprotective actions of bombesin, L-DOPA, and mild irritants: Roles of prostaglandins and sensory neurons

Background: Bombesin and dopamine prevent gastric injury by an unknown mechanism. Sensory neurons and endogenous prostaglandins play an important role in gastric mucosal defense. This study was designed to assess the role of these two local defense mechanisms in bombesin and dopamine-induced gastroprotection, as well as mild irritant-induced adaptive cytoprotection. Methods: Conscious, fasted rats were given either capsaicin (125 mg/kg subcutaneously) to ablate sensory neurons or indomethacin (5 mg/kg intraperitoneally) to inhibit prostaglandin synthesis, 2 weeks and 30 minutes, respectively, before administration of bombesin (100 μg/kg subcutaneously), the dopamine precursor L-DOPA (25 mg/kg intraperitoneally), or the mild irritant 25% ethanol (1 mL orogastric). A 1-mL orogastric bolus of acidified ethanol (150 mmol/L HCl/50% ethanol) was given 30 minutes after pretreatment with these peptides and 15 minutes after administration of the mild irritant. Rats were killed 5 minutes later and the total area of macroscopic gastric injury quantified. Results: Ablation of sensory neurons with capsaicin negated the protective actions of bombesin but failed to reverse gastroprotection by L-DOPA or 25% ethanol. Cyclooxygenase inhibition with indomethacin partially reversed bombesin and mild irritant-induced gastroprotection but did not diminish the protective actions of L-DOPA. Conclusions: Bombesin requires intact sensory neurons to exert its protective actions through a mechanism mediated, at least in part, by endogenous prostaglandins. Adaptive cytoprotection by the mild irritant 25% ethanol requires the presence of endogenous prostaglandins but not sensory neurons. L-DOPA–induced gastroprotection is independent of both local defense mechanisms. (Surgery 1998; 124:864-70.)

Role of Corticotropin-Releasing Hormone in Gastrin-Releasing Peptide-Mediated Regulation of Corticotropin and Corticosterone Secretion in Male Rats

Gastrin-releasing peptide (GRP) exerts several functions within the hypothalamus and may be involved in the regulation of pituitary hormone secretion. The purpose of this study was to investigate the central effect of GRP on hypothalamic-pituitary-adrenal axis activity in the male rat. Intracerebroventricular (i.c.v.) but not intravenous administration of GRP (1, 10, 100 ng/rat) increased plasma ACTH and corticosterone concentrations in a dose-dependent manner. The highest dose (100 ng/rat) of GRP increased plasma ACTH and corticosterone 4- and 14-fold, respectively. This increase peaked at 30–60 min after i.c.v. injection, decreased gradually and returned to baseline levels 240 min after GRP administration. The i.c.v. administration of (Leu¹³-ψ-CH₂NH-Leu¹⁴) bombesin, a competitive and specific GRP receptor antagonist, had no effect on ACTH and corticosterone secretion; however, a dose of 1 µg/rat completely blocked the increase of both hormones induced by GRP (10 ng). By using α-helical (9–41) corticotropin-releasing factor (CRF), a competitive antagonist of CRF, the role of CRF on GRP-induced ACTH and corticosterone secretion was also explored. α-Helical (9–41) CRF (10 µg/rat) blocked the increase in ACTH and corticosterone secretion induced by GRP (10 ng). The results obtained in this study suggest that GRP increases the secretion of ACTH and corticosterone in the plasma by acting centrally on GRP receptors, and that endogenous GRP receptor ligands do not tonically regulate ACTH and corticosterone secretion. Furthermore, the hypothalamus-pituitary-adrenal-activating effects induced by GRP appear to be mediated, at least in part, by CRF.

Localization and significance of pp55, a gastric mucosal membrane protein with tyrosine kinase activity.

In Fischer 344 rats, induction of gastric mucosal proliferative activity, whether the result of aging or injury or occurring after administration of epidermal growth factor, gastrin, or bombesin, is associated with a rise in tyrosine kinase activity and tyrosine phosphorylation of several mucosal proteins, including a protein with a molecular mass of 53-55 kDa. We hypothesized that this phosphotyrosine membrane protein (referred to as pp55) may play a role in regulating gastric mucosal cell proliferation and differentiation. Purification and subsequent immunoprecipitation studies now show that pp55 is a tyrosine kinase. In addition, the enzyme activity in the gastric mucosa is found to be fourfold higher in aged rats than in young rats. Incubation of gastric mucosal membranes with transforming growth factor-alpha (2 x 10(-8) M) stimulates tyrosine kinase activity of pp55. Immunolocalization studies reveal that pp55 immunoreactivity is predominantly present in mucous cells that are located just above the proliferative zone and spasmolytic peptide-immunoreactive mucous neck cells. Tyrosine kinase activity as well as expression of pp55 are also greatly increased in the gastric mucosa after hypertonic saline-induced injury, a condition that results in stimulation of surface mucosal cell proliferation and differentiation. Our current data suggest that pp55 is a tyrosine kinase, likely localized to pre-surface cells. The presence of pp55 in pre-surface mucous cells and the expression and tyrosine kinase activity of this protein, which can be stimulated during mucosal cell proliferation and differentiation, strongly suggest a role for pp55 in differentiation of gastric surface mucous cells.

The inhibition by central bombesin of peripheral stimulation of gastric secretion involves the release of nitric oxide in the dorsal motor nucleus of the vagus

Background: The neuropeptide bombesin inhibits gastric acid secretion (GAS) when administered centrally (1). Pentagastrin stimulates GAS acting on parietal cells of the stomach mucosa. Previous studies have shown that nitric oxide (NO) synthetised in the dorsal motor nucleus of the vagus (DMN) has an inhibitoy role on GAS stimulated by centrally acting agents such as distension or insulin (2). Aim: To analyse the implication of NO in the DMN in the inhibitory effects of bombesin on peripherallly stimulated GAS. Method: GAS was evaluated in rats perfused intragastrically with saline (0.9 ml min-l). Animals were placed in a stereotaxic apparatus and thereafter they received a bolus of pentagastrin (100 pg kg-l). Prior to this injection, L-NAME (80 pg kg -1) was administered locally in the DMN or in the nucleus of the tractus solitarius (NTS), and animals received an intracisternal (i.e.) administration of bombesin (40 ng kg-l). A bilateral vagotomy was performed in some experiments. Control animals were treated with vehicle (PBS) Results: (A~tEqH + 30 min -1 100 g-l; mean -+ s.e.m.; n > 6 per group)

In vivo electrochemical detection of nitric oxide release in the dorsal motor nucleus of the vagus after intracisternal administration of bombesin

In vivo electrochemical detection of nitric oxide release in the dorsal motor nucleus of the vagus after intracisternal administration of bombesin

Loss of bombesin-induced feeding suppression in gastrin-releasing peptide receptor-deficient mice.

The gastrin-releasing peptide receptor (GRP-R) is one of three members of the mammalian bombesin subfamily of seven-transmembrane G protein-coupled receptors that mediate diverse biological responses including secretion, neuromodulation, chemotaxis, and growth. The X chromosome-linked GRP-R gene is expressed widely during embryonic development and predominantly in gastrointestinal, neuronal, and neuroendocrine systems in the adult. Surprisingly, gene-targeted mice lacking a functional GRP-R gene develop and reproduce normally and show no gross phenotypic abnormalities. However, peripheral administration of bombesin at dosages up to 32 nmol/kg to such mice had no effect on the suppression of glucose intake, whereas normal mice showed a dose-dependent suppression of glucose intake. These data suggest that selective agonists for the GRP-R may be useful in inducing satiety.

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's 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 gyrus. 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.

Bombesin-Induced Pancreatic Regeneration in Pigs Is Mediated by p46Shc/p52Shc and p42/p44 Mitogen-Activated Protein Kinase Upregulation

Background: In several animal species the pancreas has the capacity to partially regenerate in a self regulating process. A complex network of growth factors modulates this process. There is evidence that bombesin stimulates pancreatic regeneration in rodents. Whether bombesin stimulates pancreas regrowth in large mammals is unknown. Shc proteins, the target of tyrosine kinase-coupled receptors, activate p42 and p44 mitogen-activated protein (MAP) kinase and induce the transcriptional upregulation of genes involved in cell proliferation. The aims of our study were to determine whether bombesin stimulates pancreatic growth in large mammals and whether this event requires Shc-MAP kinase pathway upregulation. Methods: Three groups of pigs were submitted to sham operation (group 1); to subtotal (70%) distal pancreatectomy (group 2), and to subtotal pancreatectomy followed by bombesin (5 mg three times daily) for 4 weeks (group 3). After a 4-week follow-up a second laparotomy was performed, and the residual pancreas removed. p46Shc, p52Shc and p66Shc, Grb2, and p42/p44 MAP kinase expression and phosphorylation were measured either in freshly isolated pancreatic acinar cells or whole pancreatic extracts. Results: In vivo bombesin administration resulted in: 1) ~100% growth of pancreatic duodenal lobe; 2) rapid recovery from exocrine pancreatic failure; and 3) a threefold increase in the rate of pancreatic acinar cell proliferation. Incubating freshly isolated pancreatic acinar cells with bombesin resulted in time- and concentration-dependent stimulation of p46Shc/p52Shc phosphorylation, Shc-Grb2 complex formation, and p42/p44 MAP kinase activation. In vivo bombesin administration significantly upregulated p46Shc/p52Shc and MAP kinase expression and/or activity in whole pancreatic extracts. Conclusions: In vivo chronic bombesin administration stimulates pancreatic regeneration after pancreatectomy in large mammals. Bombesin-stimulated pancreatic growth is associated with upregulation of the Shc-Grb2-SOS-Ras-MAP kinase pathway.

Bombesin Affects the Central Nervous System to Produce Sodium Intake Inhibition in Rats

de Caro, G., C. Polidori, J. V. Menani and A. K. Johnson. Bombesin affects the central nervous system to produce sodium intake inhibition in rats. PHYSIOL BEHAV 63(1) 15–23, 1998.—Bombesin (BN) elicits in the rat important behavioural modifications, including inhibition of food and of water intake. Recently, it has been observed that the peptide also inhibits the intake of sodium chloride. To state whether BN possesses a selective antinatriorexic effect or it elicits only an aspecific depression of ingestive behaviour, we studied the effects of this peptide on the intake of sodium, water or sucrose of Wistar rats after injections into the fourth brain ventricle or into selected brain areas involved in the control of sodium intake, containing BN-like peptides and/or their precursors or specific receptors. We observed that: a) BN (100–200 ng/rat) injected into the fourth brain ventricle inhibits not only the intake of 2% NaCl of sodium depleted rats but also that of water and of 5% sucrose; b) BN (5–50 ng/rat) administered into the nucleus of the solitary tract and the medial amygdala does not influence the intake of these fluids and c) BN (5–50 ng/rat) injected into the paraventricular nucleus does not influence the intake of water and 5% sucrose but potently inhibits that of 2% NaCl. We concluded that the inhibitory effect elicited on salt intake by intracranial administration of BN is selective for this behaviour and is not the expression of an aspecific depression of ingestive behaviour.

BRAIN HISTAMINE MEDIATES THE BOMBESIN-INDUCED CENTRAL ACTIVATION OF SYMPATHO-ADRENOMEDULLARY OUTFLOW

Intracerebroventricular (i.c.v.) administration of bombesin (0.3 mmol) increased plasma levels of both adrenaline and noradrenaline in urethane anesthetized rats. These bombesin-induced increases were inhibited by i.c.v. pretreatment with pyrilamine, an H 1-receptor antagonist. Ranitidine, an H 2-receptor antagonist also inhibited the increase of adrenaline, however, its effective dose was much larger than that of pyrilamine. Furthermore, the bombesin-induced increase of noradrenaline was not effectively inhibited by ranitidine. In the next series, turnover of histamine was assessed by measuring accumulation of tele-methylhistamine (t-MH), a major metabolite of brain histamine. I.c.v. administration of bombesin (0.3–3 nmol) increased turnover of hypothalamic histamine, while its intravenous administration was without effect. The present results suggest that the bombesin-induced central activation of sympatho-adrenomedullary outflow is probably, at least in part, mediated through brain histaminergic neurons.

Pharmaco-ontogeny of bombesin's suppression of food intake and its attenuation by histamine H 3 receptor agonists

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 H 3 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 H 3 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.), H 3 receptor agonists alone ( α-MH or Imetit (3 or 5 mg/kg s.c.)) or the combination of BN and H 3 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 H 3 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).

Bombesin Inhibits Histamine Release from the Rat Oxyntic Mucosa by a Somatostatin-dependent Mechanism

Background and methods: This study examines the effect of bombesin on endogenous somatostatin and the histamine-synthesizing enterochromaffin-like cells. Somatostatin and histamine were measured in the venous effluent of isolated/antrectomized vascularly perfused rat stomachs after administration of bombesin and gastrin alone or combined. Histidine decarboxylase (HDC) enzyme activity and mRNA abundance were measured in the gastric corpus after intravenous administration of bombesin to conscious rats. Results: Bombesin released somatostatin from the isolated stomachs and reduced basal and gastrin-stimulated venous histamine. Somatostatin antiserum partially reversed the effect of bombesin on basal and gastrin-stimulated histamine release. In conscious fed rats, intravenous bombesin doubled serum gastrin concentrations and increased HDC activity. Conclusion: We conclude that endogenous (paracrine) somatostatin inhibits basal and gastrin-stimulated histamine release from the ECL cell. In intact animals this effect is surmountable by simultaneously released gastrin, suggesting that a balance between the effects of gastrin and somatostatin determines the activation of the ECL cell.

Effects of bombesin on behavioral thermoregulation in the bullfrog.

Bombesin is a member of a class of neuroactive chemicals that have potent thermoregulatory effects in ectothermic and endothermic vertebrate species. Bombesin-like peptides are found in the brains of ectothermic and endothermic vertebrates and have been implicated in the central nervous system modulation of behavioral thermoregulation. Amphibians rely on behavioral thermoregulation to maintain their body temperature within developmental stage-dependent critical limits. To investigate the influence of bombesin on behavioral thermoregulation, we examined the effects of central injections of bombesin on thermal habitat selection at different stages of bullfrog development. Tadpoles and adult male and female frogs were allowed to select a preferred temperature, within an aquatic thermal gradient, before and after receiving an intracerebroventricular injection of bombesin. In larval and adult female bullfrogs, bombesin administration caused a decrease in preferred temperature values. This effect was clearly dose-dependent in tadpoles. Bombesin effects were variable in adult males, probably due to an overriding stress response to handling exhibited by males. The bombesin-induced hypothermia was blocked by [D-Phe6, Des-Met14]-bombesin (6-14), ethyl amide, a bombesin/gastrin-releasing peptide receptor antagonist. These data suggest that bombesin/gastrin-releasing peptide receptors are functional in the central nervous system of larval and adult amphibians and that receptor binding can modulate thermoregulation. They raise the question: under what natural conditions is endogenous bombesin/gastrin-releasing peptide released in the brain to activate thermoregulatory behavior?

Caudal hindbrain neuromedin B-preferring receptors participate in the control of food intake.

Recent studies have identified two subtypes of bombesin (BN) receptors in the rat central nervous system: gastrin releasing-peptide (GRP) preferring and neuromedin B (NMB) preferring. To investigate a role for the NMB-preferring receptor subtype in feeding suppression elicited by fourth ventricular (4V) BN administration, we evaluated the ability of a selective NMB-preferring receptor antagonist, BIM-23127, to block suppression of glucose intake produced by 4V BN (10 pmol). Our results showed that 4V administration of BIM-23127 dose dependently antagonized the suppression of glucose intake produced by 4V BN. In addition, 4V administration of BIM-23127 alone increased glucose intake above that observed in the baseline condition. These results support a role for the NMB-preferring BN receptor subtype in the suppression of intake produced by 4V BN administration and suggest that endogenously released NMB participates in ingestive control.

Effect of bombesin on impairment of upper respiratory tract immunity induced by total parenteral nutrition.

To determine the effect of the neuropeptide bombesin on total parenteral nutrition-induced impairment of upper respiratory tract immunity. Randomized, controlled trial. Thirty-six adult male Institute for Cancer Research mice weighing 25 to 35 g. Mice were inoculated intranasally with H1N1 virus. At 3 weeks, mice were randomized to receive chow plus intravenous saline (n = 12), intravenous total parenteral nutrition (n = 12), or intravenous total parenteral nutrition plus bombesin (n = 12) administered 3 times daily at 15 micrograms/kg. After 5 days, mice were rechallenged with intranasal virus and killed at 40 hours to determine viral shedding from the respiratory tract; normal convalescent mice do not shed virus because of intact IgA-mediated mechanisms. Viral shedding was determined by collection of nasal secretions. Samples were diluted and incubated with a suspension of Madin-Darby canine kidney cells. Viral growth was determined by hemagglutination. Body weight was similar between the total parenteral nutrition and bombesin groups; however, both were significantly lower than that in the chow group (P < .05). After 6 days of feeding, no mice in the chow group shed virus, compared with 6 (50%) of the mice in the total parenteral nutrition group. Of the mice in the bombesin group, only 1 was positive for viral shedding. The total parenteral nutrition group showed increased viral shedding compared with both the chow group (P < .01) and the bombesin group (P < .05). Exogenous administration of bombesin reversed the total parenteral nutrition-associated impairment of upper respiratory tract immunity to an IgA-mediated infectious challenge. These observations support the concept of a common mucosal immune system, since neuropeptides are endogenous to the gastrointestinal and respiratory tracts. Hormonal modulation of immunity is a promising avenue of treatment for patients who require total parenteral nutrition.

Brain prostaglandins mediate the bombesin-induced increase in plasma levels of catecholamines

Intracerebroventricular (i.c.v.) administration of bombesin (0.1, 1.0, 10.0 nmol/animal) in urethane-anesthetized rats induced long-lasting and dose dependent increases in plasma levels of adrenaline and noradrenaline. These effects of bombesin were inhibited by i.c.v. pretreatment with indomethacin (50–500 μg/animal), while the same dose of indomethacin by the intravenous route was without effect. The bombesin-induced increases in plasma levels of catecholamines were also inhibited by i.c.v. pretreatment with diclofenac (100–500 μg/animal), a cyclooxygenase inhibitor other than indomethacin. I.c.v. administration of thyrotropin releasing hormone (TRH) (10 nmol/animal) also induced increases in plasma levels of adrenaline and noradrenaline, however, these increases were not modified by i.c.v. pretreatment with indomethacin. The present results suggest that the bombesin-induced increases in plasma levels of catecholamines are probably due to prostaglandins synthetized in the brain with this neuropeptide. Furthermore, it is likely that prostaglandins are not always involved in central activation of sympatho-adrenomedullary system by other brain neuropeptides.

Triamterene Suppresses Bombesin‐enhanced Peritoneal Metastasis of Intestinal Adenocarcinomas Induced by Azoxymethane

The effects of combined administration of bombesin and the diuretic triamterene on the incidence of peritoneal metastasis of intestinal cancers induced by azoxymethane (AOM) and the labeling index of intestinal cancers were investigated in male inbred Wistar rats. From the start of the experiment, rats were given weekly s.c. injections of AOM (7.4 mg/kg body weight) for 10 weeks and s.c. injections of bombesin (40 μg/kg body weight) every other day, and from week 16, s.c. injections of triamterene (10 and 20 mg/kg body weight) every other day until the end of the experiment in week 45. Bombesin significantly increased the incidence of intestinal tumors and cancer metastasis to the peritoneum in week 45. It also significantly increased the labeling index of intestinal cancers. Although administration of both doses of triamterene with bombesin had little or no influence on the enhancement of intestinal carcinogenesis by bombesin, or the location, histologic type, depth of invasion, or labeling index of intestinal cancers, it significantly reduced the incidence of cancer metastasis. These findings indicate that triamterene suppresses cancer metastasis through a mechanism that does not affect the proliferation of intestinal cancers.

Suppression by amiloride of bombesin‐enhanced peritoneal metastasis of intestinal adenocarcinomas induced by azoxymethane

The effects of concomitant administration of bombesin and of the diuretic drug amiloride on the development of large and small intestinal tumors induced by azoxymethane (AOM), the incidence of their metastasis to the peritoneum and the labeling index of intestinal adenocarcinomas were investigated in inbred Wistar rats. From the start of the experiment, rats were given weekly s.c. injections of AOM for 10 weeks and s.c. injections of bombesin and/or a higher or lower dose of amiloride hydrochloride (amiloride) every other day until the end of the experiment in week 45. Administration of bombesin significantly increased the incidence of intestinal tumors and cancer metastasis to the peritoneum in week 45. It also significantly increased the labeling index of intestinal adenocarcinomas. Although administration of both doses of amiloride with bombesin had little or no influence on the enhancement of intestinal tumorigenesis by bombesin, the location, histological type, depth of involvement or labeling index of intestinal adenocarcinomas, a higher dose of amiloride significantly reduced the incidence of cancer metastasis to the peritoneum. Our findings indicate that amiloride possesses an anti-metastatic activity.

Bombesin acts in the suprachiasmatic nucleus to affect circadian changes in tuberoinfundibular dopaminergic neuron activity and prolactin secretion

Central administration of bombesin has been shown to block the afternoon PRL surge. A circadian change in the activity of tuberoinfundibular dopaminergic (TIDA) neurons that coincides with the onset of the PRL surge has also been found. Whether bombesin acts on the TIDA neuron to affect the PRL surge and where bombesin acts were the focuses of this study. Bombesin (0.75 microgram/3 microliters.rat) was first injected into the lateral cerebroventricle of estrogen-primed ovariectomized rats at 1200 h through preimplanted cannulas. Both the PRL surge and the circadian changes in TIDA neuron activity (using both 3,4-dihydroxyphenylacetic acid concentration and 3,4-dihydroxyphenylalanine accumulation in the median eminence as indexes) were blocked by the treatment. In suprachiasmatic nucleus-lesioned rats, however, both rhythms were absent, and the injection of bombesin exhibited no significant effect. Using microinjection of bombesin (50 ng/0.2 microliter) bilaterally into either the suprachiasmatic or arcuate nuclei at 1200 h, only the former injection effectively blocked both TIDA neuron activity and the PRL surge. We conclude that bombesin may act on the rhythm generation center, the suprachiasmatic nucleus, to exert its effect to disrupt TIDA neuron activity and the PRL surge.

Bombesin acts in the suprachiasmatic nucleus to affect circadian changes in tuberoinfundibular dopaminergic neuron activity and prolactin secretion.

Central administration of bombesin has been shown to block the afternoon PRL surge. A circadian change in the activity of tuberoinfundibular dopaminergic (TIDA) neurons that coincides with the onset of the PRL surge has also been found. Whether bombesin acts on the TIDA neuron to affect the PRL surge and where bombesin acts were the focuses of this study. Bombesin (0.75 microgram/3 microliters.rat) was first injected into the lateral cerebroventricle of estrogen-primed ovariectomized rats at 1200 h through preimplanted cannulas. Both the PRL surge and the circadian changes in TIDA neuron activity (using both 3,4-dihydroxyphenylacetic acid concentration and 3,4-dihydroxyphenylalanine accumulation in the median eminence as indexes) were blocked by the treatment. In suprachiasmatic nucleus-lesioned rats, however, both rhythms were absent, and the injection of bombesin exhibited no significant effect. Using microinjection of bombesin (50 ng/0.2 microliter) bilaterally into either the suprachiasmatic or arcuate nuclei at 1200 h, only the former injection effectively blocked both TIDA neuron activity and the PRL surge. We conclude that bombesin may act on the rhythm generation center, the suprachiasmatic nucleus, to exert its effect to disrupt TIDA neuron activity and the PRL surge.