The Effects of Deleting the Mouse Neurotensin Receptor NTR1 on Central and Peripheral Responses to Neurotensin

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 300; no. 1; pp. 305 - 313
• Main Authors: Pettibone, Douglas J., Hess, J. Fred, Hey, Patricia J., Jacobson, Marlene A., Leviten, Michael, Lis, Edward V., Mallorga, Pierre J., Pascarella, Danette M., Snyder, Melissa A., Williams, Jacinta B., Zeng, Zhizhen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2002; American Society for Pharmacology and Experimental Therapeutics
• Subjects: Analgesics - pharmacology; Animals; Blotting, Northern; Body Temperature - drug effects; Cell Line; Central Nervous System - drug effects; Gastrointestinal Motility - drug effects; In Situ Hybridization; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurotensin - pharmacology; Pain Measurement - drug effects; Peripheral Nervous System - drug effects; Phenotype; Postural Balance - drug effects; Psychomotor Performance - drug effects; Radioligand Assay; Receptors, Neurotensin - genetics; Receptors, Neurotensin - physiology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis; SSC; NT1R; SR48692; NT; RT-PCR; CHO; SR142948A; ES; PCR; bp
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.300.1.305

Mice deficient in the neurotensin (NT)-1 receptor (NTR1) were developed to characterize the NT receptor subtypes that mediate various in vivo responses to NT. F2 generation (C57BL6/Sv129J) NTR1 knockout (−/−) mice were viable, and showed normal growth and overt behavior. The −/− mice lacked detectable NTR1 radioligand binding in brain, whereas NTR2 receptor binding density appeared normal compared with wild-type (+/+) mice. The gene deletion also resulted in the loss of NTR1 expression as determined by reverse transcription-polymerase chain reaction and in situ hybridization. Intracerebroventricular injection of NT (1 μg) to +/+ mice caused a robust hypothermic response (5–6°C) and a significant increase in hot-plate latency. These effects were absent in the −/− mice. Similar results were obtained with i.p. injections of the brain-penetrant NT analog NMe-Arg-Lys-Pro-Trp-Tle-Leu (NT-2, 1 mg/kg i.p.). NT-2 administration also impaired rotarod performance in wild-type mice, but had no effect on motor coordination in knockout mice. In vitro, NT and NT-2 at 30 nM caused predominantly contraction and relaxation in isolated distal colon and proximal ileum, respectively, from +/+ mice, but no responses were observed with tissues from −/− mice. A similar loss of the contractile effects of NT was observed in the isolated stomach fundus from the knockout mice. In vivo, NT-2 administration reduced colonic propulsion substantially in wild-type mice. In contrast, NT-2 had no effect in NTR1 null mice, whereas the hypomotility effect of clonidine was intact. These data indicate that NTR1 mediates several of the central and peripheral effects of NT.