OBJECTIVES: Neurotensin (NT), of which functions are evoked by its interaction with neurotensin receptors (NTR), coexists with mesolimbic dopamine and regulates endogenous dopamine release. Recent studies have shown that NT with NTR exerts neuroleptic-like activity within the central nervous system and may play an important role in the pathogenesis and in the treatment of schizophrenia. We have examined the genetic association between schizophrenia and tetranucleotide repeat polymorphism in the 3'-flanking region of the NTR gene to investigate the possible contribution of the NTR gene to the schizophrenia susceptibility. METHODS: Among 23 alleles identified, the subjects were 120 patients (male 91, female 29) with schizophrenia and 106 normal healthy controls (male 84, female 22). They were unrelated native Korean. PANSS was used to determine positive or negative subgroup in the schizophrenic patients.Using polymerase chain reaction and polyacrylamide gel electrophoresis, tetranucleotide repeat polymorphism (CCTT and CTTT) in the 3'-flanking region of NTR gene was observed. For a comparison of NTR gene's allelic frequencies between patients with schizophrenia and normal healthy controls, chi-square test and Bonferroni's correction was performed. RESULTS: The frequency of A10 allele (base pair size=399) was significantly higher in normal healthy controls than schizophrenia (x2=16.4902, df=1, p<.000). In the comparison between schizophrenic patients with negative symptoms and normal controls, the frequency of A10 allele was significantly higher in normal healthy control subjects than patients with schizophrenia (x2=21.33, df=1, p<0.001). In the case of male, the frequency of A10 allele of schizophrenia was significantly higher than normal controls (x2=13.71, df=1, p<0.001). CONCLUSIONS: NTR gene was negatively associated with schizophrenia. NTR gene's tetranucleotide repeat polymorphism may provide some protective function against schizophrenia.
Alleles ; Central Nervous System ; Dopamine ; Electrophoresis, Polyacrylamide Gel ; Female ; Humans ; Male ; Microsatellite Repeats ; Neurotensin* ; Polymerase Chain Reaction ; Receptors, Neurotensin* ; Schizophrenia*

BACKGROUND/AIMS: Neurotensin is a gut-brain peptide with both inhibitory and excitatory actions on the colonic musculature; our objective was to understand the implications of this for motor patterns occurring in the intact colon of the rat. METHODS: The effects of neurotensin with concentrations ranging from 0.1-100 nM were studied in the intact rat colon in vitro, by investigating spatio-temporal maps created from video recordings of colonic motility before and after neurotensin. RESULTS: Low concentration of neurotensin (0.1-1 nM) inhibited propagating long distance contractions and rhythmic propagating motor complexes; in its place a slow propagating rhythmic segmental motor pattern developed. The neurotensin receptor 1 antagonist SR-48692 prevented the development of the segmental motor pattern. Higher concentrations of neurotensin (10 nM and 100 nM) were capable of restoring long distance contraction activity and inhibiting the segmental activity. The slow propagating segmental contraction showed a rhythmic contraction—relaxation cycle at the slow wave frequency originating from the interstitial cells of Cajal associated with the myenteric plexus pacemaker. High concentrations given without prior additions of low concentrations did not evoke the segmental motor pattern. These actions occurred when neurotensin was given in the bath solution or intraluminally. The segmental motor pattern evoked by neurotensin was inhibited by the neural conduction blocker lidocaine. CONCLUSIONS: Neurotensin (0.1-1 nM) inhibits the dominant propulsive motor patterns of the colon and a distinct motor pattern of rhythmic slow propagating segmental contractions develops. This motor pattern has the hallmarks of haustral boundary contractions.
Absorption ; Animals ; Baths ; Colon* ; In Vitro Techniques ; Interstitial Cells of Cajal ; Lidocaine ; Myenteric Plexus ; Neural Conduction ; Neurotensin* ; Peristalsis ; Rats* ; Receptors, Neurotensin ; Video Recording

As a neuropeptide, neurotensin (NTS) is widely expressed in central and peripheral nervous system, which is mainly mediated byneurotensin receptor1 (NTSR1) to activate the related downstream signaling pathways. After summarized the function and mechanism of NTS/NTSR1 in various malignant tumors, we found that NTS/NTSR1 played essential roles during tumor initiation and development. NTS/NTSR1 regulates tumor initiation, proliferation, apoptosis, metastasis and differentiation mainly through three pathways, including IP3/Ca2+ /PKC/MAPKs pathway, MMPs/EGFR/MAPKs (PI3K/Akt) pathway, or Rho-GTPsaes and non-receptor tyrosine kinase pathway. Besides, NTS/NTSR1 is also regulated by some upstream pathways and some traditional Chinese medicine preparations and traditional Chinese medicine therapies. In this article, we summarized the function of NTS/NTSR1 and its mechanisms, and discussed the prospective in its application to clinical diagnosis and drugs targeting.
Animals ; Humans ; Medicine, Chinese Traditional ; Neoplasms ; etiology ; Neurotensin ; chemistry ; physiology ; Receptor, Epidermal Growth Factor ; physiology ; Receptors, Neurotensin ; chemistry ; physiology ; Signal Transduction ; physiology ; rhoA GTP-Binding Protein ; physiology

BACKGROUND/AIMS: Although neurotensin (NT) stimulates colon motility and the passage of intestinal contents, the associated mechanism of action remains unclear. The objective of this study was to investigate the effects of NT on colon motility using isolated rat colon. METHODS: Intraluminal pressure was measured at both the proximal and distal portions of the isolated colon. An isolated rat colon was perfused with Krebs solution via the superior mesenteric artery. After stabilization, NT was administered in concentrations of 14, 28, 138 and 276 pM. After pretreatment with phentolamine, propranolol, hexamethonium, atropine or tetrodotoxin, NT was administered at a concentration of 276 pM, and then the intraluminal pressure was monitored. RESULTS: NT significantly increased colon motility at concentrations of 14, 28, 138, and 276 in the proximal colon (25.1+/-6.5%, 175.4+/-117.0%, 240.8+/-115.1% and 252.3+/-110.6%, respectively) and in the distal colon (35.6+/-11.8%, 97.5+/-35.1%, 132.7+/-36.7% and 212.1+/-75.2%, respectively). The stimulant effect of NT was more potent in the proximal colon, in a concentration-dependent manner (P<0.05). The stimulant effect of NT was significantly inhibited by atropine at both the proximal and distal colon and by tetrodotoxin at the proximal colon, but not by tetrodotoxin at the distal colon and not by propranolol, phentolamine, or hexamethonium at both the proximal and distal colon. CONCLUSIONS: NT increased colon motility at both the proximal and distal portions of the rat colon. The effects were more prominent at the proximal portion. The results of this study suggest that the stimulant action of NT may be mediated by local cholinergic muscarinic receptors.
Animals ; Atropine ; Autonomic Pathways ; Colon ; Gastrointestinal Contents ; Hexamethonium ; Isotonic Solutions ; Mesenteric Artery, Superior ; Neurotensin ; Phentolamine ; Propranolol ; Rats ; Receptors, Muscarinic ; Tetrodotoxin

Neurotensin receptor-1 (NTR1), which can stimulate the intracellular cascade signal pathway, belongs to the large superfamily of G-protein coupled receptors. NTR1 is related to the occurrence and development of several kinds of diseases. In order to screen the inhibitors for the cancers associated with NTR1 protein, we established a CHO (Chinese hamster ovary) cell line in which human neurotensin receptor-1 was highly expressed. The method is to construct the recombinant plasmid which was lysed with the hNTR1 gene and transfect it into CHO cells. After selected with G418, the cell line was evaluated by Western blotting analysis and calcium flux assays. Through the calcium flux assays on FlexStation 3, we got the EC50 value of neurotensin peptide which is the natural NTR1 agonist, and the IC 50 value of SR48692 which is the known NTR1 antagonist. The established human CHO/NTR1 cell line can be used to study the profile of NTR1 biological activity and further screen of NTR1 antagonists and agonists.
Animals ; CHO Cells ; Calcium Signaling ; Cricetinae ; Cricetulus ; Humans ; Pyrazoles ; pharmacology ; Quinolines ; pharmacology ; Receptors, Neurotensin ; antagonists & inhibitors ; genetics ; metabolism ; Transfection

A complex set of brain based systems modulate feeding to maintain constant body weight. The adipose derived-hormone, leptin, plays a crucial role in this control by acting on diverse leptin receptor (LepRb)-expressing neurons in the hypothalamus and brainstem to modify behavior and metabolism. In addition to controlling energy expenditure and satiety, leptin controls motivation and the reward value of food by regulating two interconnected systems: hypocretin (HCRT) neurons and the mesolimbic dopamine (MLDA) system. Modest/acute decreases in leptin levels, as associated with mild caloric restriction, increase MLDA activity and overall food-seeking behavior; in contrast, severe starvation or complete leptin deficiency blunt MLDA activity, along with motivation and associated behaviors. Lateral hypothalamic (LHA) LepRb neurons project to dopamine (DA) neurons in the ventral tegmental area, where neurotensin (NT) release augments MLDA function; these LepRb(NT) cells also innervate HCRT neurons to control Hcrt expression and inhibit HCRT neurons. Ablation of LepRb in these cells abrogates the control of HCRT cells by leptin and decreases activity and MLDA function. We propose that this neural pathway regulates the MLDA, activity, and motivation in response to leptin and nutritional status.
Body Weight ; Brain ; Brain Stem ; Caloric Restriction ; Dopamine ; Energy Metabolism ; Hypothalamus ; Leptin ; Metabolism ; Motivation ; Neural Pathways ; Neurons ; Neurotensin ; Nutritional Status ; Obesity ; Orexins ; Receptors, Leptin ; Reward ; Starvation ; Ventral Tegmental Area