Infusion Of Neurotensin Research Articles

77-OR: The Gut Peptide Neurotensin Does Not Reduce Appetite and Food Intake in Healthy Young Men

Background: Altered meal-associated secretion of gut peptides is key for the metabolic changes and weight-loss observed after Roux-en-Y gastric bypass (RYGB). Parenteral administration of the gut peptide neurotensin (NT) reduces food intake in rodents, and, like glucagon-like peptide-1 and peptide YY, the secretion of NT is markedly increased after RYGB. We therefore investigated the effect of intravenous (IV) NT on ad libitum food intake and appetite sensations. Design: Using a double-blinded, randomized placebo-controlled design, NT (2.5pmol/kg/min) or saline was infused IV in healthy young men to obtain NT concentrations similar to NT levels observed postprandially after RYGB. Four visits were performed in random order, after an acclimatization visit, to evaluate the main outcomes - ad libitum food intake and appetite sensations (visual analogue scale (VAS) questionnaires). Blood samples were collected for plasma and serum analyses (including entero-pancreatic peptides and glucose). NT or saline was infused after a basal period (t= -60 to 0 min). On two study days (n=18), an ad libitum meal was served after one hour of infusion (t= 60 min) followed by blood sampling/VAS until t= 120 min (infusion discontinued). On two other study days (n=16), a liquid mixed meal was ingested after one hour of infusion (t = 60 min) followed by blood sampling and VAS until an ad libitum meal was served at t= 240 min (infusion discontinued at t=270min). Results: Food intake was similar on the ad libitum meal (t = 60 min) days - NT (4150 (3607-4696)kJ, mean (95% confidence interval) vs. saline (3820 (3250-4405) kJ, P=0.062 (paired t-test)) and on the LMM + ad libitum meal (t= 240 min) days - NT (4320 (3698-5008)kJ vs. saline (4250 (3739-4870)kJ, P=0.80). NT infusions did not influence appetite sensations or elicit gastrointestinal side effects. Conclusions: Despite obtaining NT concentrations similar to what is observed postprandially after RYGB, we did not observe any differences in appetite sensations or food intake. Disclosure S. Veedfald: None. C. Martinussen: None. M.S. Svane: None. T. Justinussen: None. M.G. Hindsø: None. N. Hedbäck: None. C.B. Christiansen: None. N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S, Novo Nordisk Foundation. Speaker’s Bureau; Self; Merck Sharp & Dohme Corp. K.N. Bojsen-Moller: None. B. Hartmann: None. M. Fenger: None. J.F. Rehfeld: None. S. Madsbad: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. J.J. Holst: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Zealand Pharma A/S. Other Relationship; Spouse/Partner; Antag Therapeutics. Funding Desirée og Niels Ydes Fond; Læge Sophus og hustru Olga Friis Legat; Beckett Fonden; Hørslev Fonden; Aase og Ejnar Danielsens Fond; Fabrikant Frands Køhler Nielsen og hustrus legat; Carl og Ellen Hertz’ Legat

Widely Distributed Neurotensinergic Neurons in the Brainstem Regulate NREM Sleep in Mice.

Classical transection studies suggest that, in addition to the hypothalamus, the brainstem is essential for non-rapid eye movement (NREM) sleep. The circuits underlying this function, however, have remained largely unknown. We identified a circuit distributed in the midbrain, pons, and medulla that promotes NREM sleep in mice. We focused on the sublaterodorsal tegmentum, an area implicated in dual regulation of REM and NREM sleep. Transcriptomic and genetic analyses revealed that neurons positive for the neuropeptide neurotensin promote NREM sleep. Further analyses identified downstream NREM sleep-promoting neurons in the dorsal deep mesencephalic nucleus, the lateral part of theperiaqueductal gray, and the medial vestibular nucleus that were also neurotensinergic. Infusion of neurotensin into the fourth ventricle induced NREM sleep-like cortical activity, whereas mice deficient for neurotensin exhibited increased REM sleep, implicating the involvement of the neuropeptide itself. These findings identify a widely distributed NREM sleep-regulating circuit in the brainstem with a common molecular property.

Effects of pallidal neurotensin on haloperidol-induced parkinsonian catalepsy: behavioral and electrophysiological studies

The globus pallidus plays a critical role in movement regulation. Previous studies have indicated that the globus pallidus receives neurotensinergic innervation from the striatum, and systemic administration of a neurotensin analog could produce antiparkinsonian effects. The present study aimed to investigate the effects of pallidal neurotensin on haloperidol-induced parkinsonian symptoms. Behavioral experiments and electrophysiological recordings were performed in the present study. Bilateral infusions of neurotensin into the globus pallidus reversed haloperidol-induced parkinsonian catalepsy in rats. Electrophysiological recordings showed that microinjection of neurotensin induced excitation of pallidal neurons in the presence of systemic haloperidol administration. The neurotensin type-1 receptor antagonist SR48692 blocked both the behavioral and the electrophysiological effects induced by neurotensin. Activation of pallidal neurotensin receptors may be involved in neurotensin-induced antiparkinsonian effects.

Effect of intracerebroventricular infusion of neurotensin in glucose-dependent insulinotropic peptide secretion in dogs

GIP is a major physiological component of the enteroinsular axis. Several researchers have pointed to a neural regulation of GIP secretion. We have previously studied the effect of intracerebroventricular (icv) infusion of insulin, NPY and bombesin in the regulation of GIP secretion. The aim of the present study is to evaluate a possible role of neurotensin in neural regulation of GIP secretion. Thirty-two adult dogs were used in this study. In a dose–response study (experiment 1) we used 3 different doses of neurotensin (25, 50 and 100μg) in a bolus icv infusion. In experiment 2 the animals received a bolus icv infusion of 50μg neurotensin and an equivalent amount of artificial cerebrospinal fluid (aCSF) at 1-week interval. In experiment 3 the animals received a continuous icv infusion of neurotensin at a constant rate of 1μg/kg/h and aCSF over a 3-h period, at 1-week interval. In experiment 4 the experiment of group 3 was repeated with a simultaneous intraduodenal infusion of a glucose load through the Mann-Bollman fistula. Plasma levels of glucose, insulin and GIP were assayed. Results: Bolus and continuous icv infusion of neurotensin produced a significant increase in glucose, GIP and insulin levels. In the 4th experiment icv infusion of neurotensin produced a more prominent increase of glucose and insulin levels compare to infusion of aCSF. GIP levels were lower after infusion of neurotensin compared to aCSF. Conclusions: Our data suggest a differential effect of neurotensin on GIP secretion, dependent on the energy load.

Effects of chronic infusion of neurotensin and a neurotensin NT1 selective analogue PD149163 on amphetamine-induced hyperlocomotion

Neurotensin (NT) has been proposed as an endogenous antipsychotic based in part on the similarity in behavioural effects to antipsychotic drugs, for example, attenuation of both amphetamine-induced hyperlocomotion (AH) and amphetamine disrupted pre-pulse inhibition in the rat. However, there is some evidence that repeated administration of NT or an analogue produces behavioural tolerance to such effects. The present experiments sought to confirm and extend these findings by testing the effects on AH of 7 days central administration of NT and the NT1 selective analogue PD 149163 and the effects of 21 days central administration of NT. NT and PD149163 continuously administered for 7 days produced no effect on AH (in contrast to attenuation with a single injection here and previously reported), whereas 21 days of NT administration potentiated AH. Together, these studies report that the effects of NT or a NT analogue on AH depends on the duration of administration of peptide. The results are discussed in comparison with the reported antipsychotic properties of acute administration of NT and possible mechanisms involving NT1 receptors.

Time course of the hypothermic response to continuously administered neurotensin

Intracerebroventricular administration of the tridecapeptide neurotensin is known to elicit hypothermia in rodents for few hours. In the present study, we investigated a continuous intracerebroventricular infusion regimen for prolongation of the hypothermic effect. Male Wistar-Han rats (n=13) received neurotensin 10-50 microg/h for 48 h, while their body temperature was monitored continuously. This protocol led to a dose-dependent decrease of body temperature down to 35-36 degrees C. The nadir of hypothermia lasted for approximately 4h and normothermia was re-established after 12-24h. Furthermore, abundance of neurotensin in the hypothalamus was determined after 6 and 30 h by western blotting. High levels were still found at 30 h, while the rats had already become normothermic at that time. In summary, continuous infusion of neurotensin led to prolongation of the known hypothermic response, however resulted in development of tolerance.

Neuropeptide neurotensin stimulates intestinal wound healing following chronic intestinal inflammation

Because neurotensin (NT) and its high-affinity receptor (NTR1) modulate immune responses, chloride secretion, and epithelial cell proliferation, we sought to investigate their role in the repair process that follows the development of mucosal injuries during a persistent inflammation. Colonic NT and NTR1, mRNA, and protein significantly increased only after dextran sodium sulfate (DSS)-induced inflammatory damage developed. Colitis-induced body weight loss, colonic myeloperoxidase activity, and histological damage were significantly enhanced by SR-48642 administration, a nonpeptide NTR1 antagonist, whereas continuous NT infusion ameliorated colitis outcome. To evaluate the NT and NTR1 role in tissue healing, mucosal inflammatory injury was established administering 3% DSS for 5 days. After DSS discontinuation, mice rapidly gained weight, ulcers were healed, and colonic NT, NTR1, and cyclooxygenase (COX)-2 mRNA levels were upregulated, whereas SR-48642 treatment caused a further body weight loss, ulcer enlargement, and a blunted colonic COX-2 mRNA upregulation. In a wound-healing model in vitro, NT-induced cell migration in the denuded area was inhibited by indomethacin but not by an antitransforming growth factor-beta neutralizing antibody. Furthermore, NT significantly increased COX-2 mRNA levels by 2.4-fold and stimulated PGE(2) release in HT-29 cells. These findings suggest that NT and NTR1 are part of the network activated after mucosal injuries and that NT stimulates epithelial restitution at least, in part, through a COX-2 dependent pathway.

Involvement of mast cells in basal and neurotensin-induced intestinal absorption of taurocholate in rats.

Neurotensin (NT), a hormone released from intestine by ingested fat, facilitates lipid digestion by stimulating pancreatic secretion and slowing the movement of chyme. In addition, NT can contract the gall bladder and enhance the enterohepatic circulation (EHC) of bile acids to promote micelle formation. Our recent finding that NT enhanced and an NT antagonist inhibited [(3)H]taurocholate ([(3)H]TC) absorption from proximal rat small intestine indicated a role for endogenous NT in the regulation of EHC. Here, we postulate the involvement of intestinal mast cells in the TC uptake process and in the stimulatory effect of NT. In anesthetized rats with the bile duct cannulated for bile collection, infusion of NT (10 pmol.kg(-1).min(-1)) enhanced the [(3)H]TC recovery rate from duodenojejunum by 2.2-fold. This response was abolished by pretreatment with mast cell stabilizers (cromoglycate, doxantrazole) and inhibitors of mast cell mediators (diphenhydramine, metergoline, zileuton). In contrast, mast cell degranulators (compound 48/80, substance P) and mast cell mediators (histamine, leukotriene C(4)) reproduced the effect of NT. N(G)-nitro-l-arginine methyl ester enhanced and l-arginine inhibited basal and NT-induced TC uptake, consistent with the known inhibitory effect of nitric oxide (NO) on mast cell reactivity. These results argue that basal and NT-stimulated TC uptake in rat jejunum are similarly dependent on mast cells, are largely mediated by release of mast cell mediators, and are subject to regulation by NO.

Endogenous neurotensin facilitates enterohepatic bile acid circulation by enhancing intestinal uptake in rats.

Initial studies on the digestive hormone neurotensin (NT) showing that intestinal NT mRNA expression and blood levels were altered in rats fed chow containing bile acid (BA) and the BA chelator cholestyramine led us to investigate the role of NT in the enterohepatic circulation of BA. In fasted, anesthetized rats with common bile ducts cannulated for bile collection, intravenous NT infusion (10 pmol. kg(-1). min(-1)) enhanced BA output relative to control over 3 h in animals administered donor bile into the duodenum (30 microl/min). This suggested that the effect of NT was on the return of BA from the intestine to the liver, which is rate determining in the normal process. In rats prepared as described above and administered [(3)H]taurocholate ([(3)H]TC; 5 mM, 1 ml) duodenally, NT infusion (3-10 pmol x kg(-1) x min(-1)) increased the [(3)H]TC recovery rate in bile approximately twofold, whereas sulfated CCK-8 (12-50 pmol x kg(-1) x min(-1)) had no effect. To investigate the roles of endogenous NT and CCK, we administered [(3)H]TC into the rat duodenum or lower jejunum and tested the effect of the NT antagonist SR-48692 (2 nmol x kg(-1) x min(-1)) or CCK-A antagonist lorglumide (100 nmol x kg(-1) x min(-1)). SR-48692 reduced the [(3)H]TC recovery rate by congruent with 50% and congruent with 24% in the duodenum and jejunum, respectively, whereas lorglumide had no effect. These results suggest that NT or a similar peptide is an endogenous regulator of enterohepatic BA cycling, which acts by enhancing BA uptake in the intestine.

Enhancement of Jejunal Absorption of Conjugated Bile Acid by Neurotensin in Rats

Release of neurotensin (NT) from intestines is markedly stimulated by ingested fat, and NT may facilitate lipid digestion and absorption through various actions that are not fully understood. Our recent finding that NT stimulates hepatic output of bile acids only when bile delivery to the intestine is maintained has led us to investigate the effects of NT on bile acid absorption in the rat small intestine. We measured the effects of intravenous infusion of NT (3-10 pmol x kg(-1) x min(-1)) on biliary recovery of (3)H-taurocholate ((3)H-TC) and (3)H-cholate administered into proximal and distal intestines or into isolated intestinal segments in situ in biliary fistula rats. To further understand the underlying mechanisms involved, the effects of NT on intestinal absorption of (3)H-D-glucose, (3)H-leucine, (14)C-antipyrine, and (51)Cr-EDTA were investigated by monitoring the absorption of radioactivity into superior mesenteric venous blood. Infusion of NT, at doses that caused near physiologic increases in blood NT levels, increased biliary recovery of (3)H-TC from the jejunum (3.4-fold) and ileum (1.7-fold), but did not enhance absorption of (3)H-cholate. NT also facilitated transcellular uptake of (3)H-glucose and (3)H-leucine and increased paracellular uptake to (51)Cr-EDTA and (3)H-mannitol, but did not alter the absorption rate for (14)C-antipyrine. These results indicate that NT can exert a facilitative effect on intestinal bile acid absorption and return to liver. This effect of NT may involve increases in paracellular absorption and carrier-mediated transport by mechanisms not yet identified.

Differential effects of neurotensin and cholecystokinin on intestinal microcirculation after ischemia-reperfusion.

We investigated the effect of neurotensin and cholecystokinin (CCK) on intestinal microcirculation after ischemia-reperfusion. Ischemia was induced in Wistar rats by occlusion of the superior mesenteric artery for 40 min. Ten minutes before reperfusion, infusion of either neurotensin or CCK was started. Afterwards, the microhemodynamics of the jejunum were examined by means of intravital microscopy. Ischemia-reperfusion decreased functional capillary density from 873.4+/-18.1 to 362.5+/-8.3 cm(-1) and red blood cell velocity from 0.49+/-0.03 to 0.34+/-0.02 mm/s. Furthermore, leukocyte-endothelium interaction was increased. Neurotensin infusion significantly increased functional capillary density to 483.2+/-9.0 cm(-1) and red blood cell velocity to 0.69+/-0.01 mm/s in the mucosal capillaries compared with ischemic controls. Despite the amelioration of villus perfusion, the number of non-perfused villi significantly increased (11.8+/-3.6%) compared with ischemic controls. CCK infusion also resulted in a significant increase of functional capillary density (535.2+/-7.4 cm(-1)) and red blood cell velocity (0.67+/-0.01 mm/s). In contrast to neurotensin, the number of non-perfused villi was not increased (5.8+/-2.2%). We conclude that neurotensin further aggravates perfusion inhomogeneity and stasis when administered during the ischemic period. In contrast, CCK has no negative influence on perfusion homogeneity after ischemia-reperfusion. It may be superior to neurotensin in the reconstitution of normal microvascular perfusion patterns after ischemia-reperfusion.

Neurotensin elevates hepatic bile acid secretion in chickens by a mechanism requiring an intact enterohepatic circulation.

Neurotensin (NT), given intravenously at 10-50 pmol/kg per min to anesthetized female chickens equipped with a bile duct fistula, dose-dependently elevated hepatic bile flow and bile acid output but only when the enterohepatic circulation was maintained by returning the bile to the intestinal lumen. Infusion of NT at 10 and 50 pmol/kg per min increased the average hepatic bile acid output over a 30-min period to 138 +/- 11 and 188 +/- 13% of control, respectively. During infusion of NT, plasma levels of immunoreactive NT (iNT) increased in time from the basal level (14 +/- 1.3 pM) to reach steady state at 30 min. There was a near linear relationship between the dose of NT infused and the increment in plasma iNT. In addition, infusion of NT at 40 pmol/kg min gave a plasma level of iNT (approximately/= 88 pM) which was within the range of those observed during duodenal perfusion with lipid (54-300 pM) and near to that measured in hepatic portal blood from fed animals (52 +/- 5 pM). Perfusion of duodenum with lipid released endogenous NT and increased the rate of hepatic bile flow. When NT antagonist SR48692 was given, bile flow rate decreased to the basal level. These results suggest that intestinal NT, released by lipid, may participate in the regulation of hepatic bile acid output by a mechanism requiring an intact enterohepatic circulation.

Neurotensin-related regulation of the postprandial lower-oesophageal-sphincter pressure.

Ingestion of food has been shown to modulate the lower-oesophageal-sphincter pressure (LESP). Fat is especially effective in decreasing the postprandial LESP. As there is good evidence that neurotensin (NT) is able to decrease the LESP, we conducted the present trial to determine whether NT could possibly be a mediator of the fat-induced decrease of the LESP. Six half-breed dogs were fitted for cervical side-to-side oesophagostomy to allow repeated oesophageal intubation; plasma NT immunoactivity was recorded during infusion of NT and after intragastric instillation of 200 ml of a fat solution. Experiments were repeated, with the specific NT antibody GN25 administered intravenously. The optimal dose of NT required to simulate a postprandial situation was 50 pmol/kg/h. Infusion of this NT dose led to a statistically significant decrease of the LESP. Simultaneous administration of the NT antibody (immunoneutralisation) significantly inhibited this effect. Intragastric fat decreased the LESP and increased plasma NT. Immunoneutralisation of endogenously released NT led to an earlier restoration of baseline LESP, but this effect was not statistically significant. NT and intragastric fat modulate the LESP. NT appears to mediate the postprandial, fat-induced decrease of the LESP. Research with specific NT-receptor antagonists is necessary to determine the exact role of NT and other regulatory peptides in this context.

Neurotensin modulates the composition of pancreatic exocrine secretions in chickens.

The effects of neurotensin on pancreatic exocrine secretion were examined in fasted, conscious White Leghorn hens. A cannula was surgically implanted in the central duct serving the ventral lobe of the pancreas in order to collect pure pancreatic juice. Following recovery, neurotensin was infused intravenously at 3.6 or 10.8 pmol/kg*min. The volume and pH of the pancreatic secretions were recorded and total pancreatic protein concentration, amylase, lipase, trypsin, and chymotrypsin activity were measured every 30 min for 2 hr and compared to secretions following the infusion of 0.9% saline. Our results demonstrated that neurotensin did not affect the pH nor the pancreatic juice protein concentration, but did increase secretion rate following neurotensin infusion at 3.6 pmol/kg*min. Amylase activity was significantly depressed during neurotensin infusions, while lipase (both pancreatic and carboxylester lipase) activity was significantly elevated. The ratio of amylase to lipase activity was especially depressed by neurotensin infusion at 10.8 pmol/kg*min. Insufficient secretory activity prevented a balanced statistical analysis of chymotrypsin activity, but from a pooled analysis, neurotensin had no effect on protease activity in the pancreatic juice. These results support our current research indicating that neurotensin may be a hormonal regulator of postprandial lipid digestion in chickens.

Neurotensin modulates the composition of pancreatic exocrine secretions in chickens

The effects of neurotensin on pancreatic exocrine secretion were examined in fasted, conscious White Leghorn hens. A cannula was surgically implanted in the central duct serving the ventral lobe of the pancreas in order to collect pure pancreatic juice. Following recovery, neurotensin was infused intravenously at 3.6 or 10.8 pmol/kg*min. The volume and pH of the pancreatic secretions were recorded and total pancreatic protein concentration, amylase, lipase, trypsin, and chymotrypsin activity were measured every 30 min for 2 hr and compared to secretions following the infusion of 0.9% saline. Our results demonstrated that neurotensin did not affect the pH nor the pancreatic juice protein concentration, but did increase secretion rate following neurotensin infusion at 3.6 pmol/kg*min. Amylase activity was significantly depressed during neurotensin infusions, while lipase (both pancreatic and carboxylester lipase) activity was significantly elevated. The ratio of amylase to lipase activity was especially depressed by neurotensin infusion at 10.8 pmol/kg*min. Insufficient secretory activity prevented a balanced statistical analysis of chymotrypsin activity, but from a pooled analysis, neurotensin had no effect on protease activity in the pancreatic juice. These results support our current research indicating that neurotensin may be a hormonal regulator of postprandial lipid digestion in chickens.

The effects of intra-accumbens neurotensin on sensorimotor gating

Neurotensin is a neuropeptide which coexists with mesolimbic dopamine. Previous studies have shown that centrally administered neurotensin can modulate the activity of mesolimbic dopamine with a profile similar to neuroleptics. For example, infusions of neurotensin into the nucleus accumbens inhibit amphetamine-induced hyperlocomotion. Prepulse inhibition (PPI) occurs when a weak prestimulus (`prepulse') inhibits the amplitude of the startle response to an intense stimulus (`pulse'). PPI is an operational measure of sensorimotor gating which is strongly regulated by mesolimbic dopamine. This study examined the effects of various doses of neurotensin infused into the nucleus accumbens of rats on the prepulse inhibition (PPI) of their acoustic startle reflex. Neurotensin (0.25–5.0 μg) was infused into the nucleus accumbens of rats. Animals then received subcutaneous injections of amphetamine (2 mg/kg) or saline and were placed in startle chambers where measures of startle amplitude and PPI were obtained. Neurotensin increased baseline PPI and blocked amphetamine-induced disruption of PPI in a dose-dependent fashion. The lowest dose of neurotensin tested (0.25 μg) significantly increased baseline PPI and both 0.25 and 1.0 μg neurotensin blocked amphetamine-induced decreases in PPI. The 5.0 μg dose of neurotensin had no significant effect on prepulse inhibition. Neurotensin had no effect on the amplitude of the acoustic startle reflex in amphetamine- or saline-treated rats. The results suggest that intra-accumbens neurotensin has a significant, dose-dependent effect on sensorimotor gating in which lower doses (0.25–1.0 μg) exhibit a neuroleptic-like action.

Cross-tolerance between ethanol and neurotensin in mice selectively bred for ethanol sensitivity

Neurotensin (NT), a tridecapeptide that satisfies criteria as a neurotransmitter, mimics many actions of ethanol, and evidence indicates that some of the acute effects of ethanol are mediated in part by NT. Recent studies have shown that chronic ethanol treatment produced a downregulation of NT receptors in mesolimbic brain regions of long sleep (LS) mice and that reduced NT binding capacity was associated with acquisition and decay of tolerance to ethanol-induced locomotor inhibition and hypothermia in these mice. The present study was undertaken to determine whether cross-tolerance develops between NT and ethanol and whether chronic NT infusion produces NT receptor downregulation. Animals chronically treated with ethanol were tolerant to NT-mediated locomotor inhibition at a dose of 1.8 pmol NT, ICV, and were tolerant to NT-induced hypothermia at 1.8 and 6.0 pmol NT. Following repeated injections or continuous infusion of NT ICV, LS mice showed tolerance to both NT-and ethanol-induced hypothermia and locomotor inhibition. Indeed, ethanol doses that are hypnotic in control mice (2.8 g/ kg) were not effective in abolishing locomotor activity following chronic NT administration. Results with chronic saline infusion ICV indicate that stress alters sensitivity to ethanol-induced hypothermia. Chronic infusion of NT ICV produced a region-specific downregulation of high-affinity NT receptors in the striatum. The results demonstrate that cross-tolerance develops between NT and ethanol, and further support a role for neurotensinergic systems in the actions of ethanol.

Changes in mouse brain neurotensin receptor density following chronic infusion of neurotensin.

Many centrally acting drugs affect neurotensin (NT) systems by increasing levels of the peptide in specific brain regions. If these changes represent increases in extracellular NT levels, then changes in NT receptors would be expected. The focus of this study was to examine the effects of continuous exposure of NT receptors to agonist. Continuous infusion of NT (0.6 or 6 nmol/h) into the lateral ventricle via an osmotic minipump for 3 days caused a significant increase (over saline infusion) in total and low-affinity NT receptor density in the cerebellum of LS mice. High-affinity NT receptor density was increased in the frontal cortex. Seven days of NT infusion (6 nmol/h) caused no changes in NT receptor density.

Trophic effects of neurotensin in massive bowel resection in the rat

The trophic effect of the administration of exogenous neurotensin on the intestinal mucosa was studied in rats following an 80% bowel resection. Villus length and mucosal DNA content were assessed in the jejunal and ileal mucosa of the remnant intestine 14 days after resection. The data obtained in an 80% resected control group (80% group) and an experimental group receiving an infusion of neurotensin (300 micrograms/kg/day) for 14 days subcutaneously (80% + NT group) were compared. The results indicate that the administration of exogenous neurotensin (80% + NT) increases villus length (jejunum: 920 +/- 77 vs 861 +/- 25 microns and ileum length: 975 +/- 23 vs 875 +/- 99 microns) to an extent greater than that observed in the 80% resected group not receiving exogenous neurotensin. The levels of mucosal DNA per milligram of protein increased significantly in both groups but was paradoxically less in the 80% + NT group than in the 80% resection group (jejunum: 8.12 +/- 0.56 vs 10.18 +/- 0.80; ileum: 8.63 +/- 0.43 vs 10.05 +/- 0.46). These data suggest that the administration of exogenous neurotensin to the rat potentiates the growth of intestinal villi and accelerates the intestinal trophic response seen following massive bowel resection. The increase in circulating enteroglucagon levels noted after neurotensin administration (80% + NT: 547 +/- 48 pg/ml vs 80%: 341 +/- 41 pg/ml) suggests that some of the trophic effects of neurotensin may be mediated, at least in part, by enteroglucagon. These data also suggest a potential role for the use of neurotensin in the initial treatment of individuals with short bowel syndrome.

Mechanism of neurotensin stimulation of external pancreatic secretion in the rat.

The gut and brain peptide neurotensin has been claimed to directly or indirectly stimulate external pancreatic secretion. The purpose of this study was to analyze the mechanism of the neurotensin effect on external pancreatic secretion in the rat. The pancreatic dose-response curve to 40-min venous infusions of neurotensin 1-13 (0.1-10 micrograms/kg-h = 0.06-6 nmol/kg-h) was biphasic; the maximal response occurred at 3.16 micrograms/kg-h and reached approximately 30% of the maximal response to cholecystokinin (CCK). The ED50 was 0.27 micrograms/kg-h (= 0.16 nmol/kg-h) for bicarbonate and 0.45 micrograms/kg-h (= 0.27 nmol/kg-h) for protein output. Pancreatic secretion in response to each neurotensin dose increased steadily during the infusion and peaked 20-40 min after the end of infusion. Atropine and hexamethonium suppressed the stimulatory effect of neurotensin on volume, bicarbonate, and total protein output (p < 0.01). The CCKA receptor antagonist L364718 decreased by 80% sodium and bicarbonate response (p < 0.01) and suppressed protein response (p < 0.01) to neurotensin. Methadone reduced the response to neurotensin by 85%, vagotomy by 80%, and capsaicin pretreatment by 70%. The blockade of alpha 1-, alpha 2-, and beta-adrenoreceptors or of CCKB receptors did not change the neurotensin effect. We conclude that the mechanism of neurotensin stimulation is indirect and neurally mediated and involves nicotinic and muscarinic synapses, CCKA receptors, and, in part, capsaicin-sensitive sensory fibers.(ABSTRACT TRUNCATED AT 250 WORDS)