Differential effects of the nonpeptide neurotensin antagonist, SR 48692, on the pharmacological effects of neurotensin agonists

doi:10.1016/0196-9781(94)00146-W

Peptides

Volume 16, Issue 1, 1995, Pages 37-44

https://doi.org/10.1016/0196-9781(94)00146-W Get rights and content

Abstract

In in vitro studies, SR 48692, a nonpeptide neurotensin receptor antagonist, inhibited the binding of [³H] or [¹²⁵I]neurotensin to membrane preparations from 10-day-old mouse brains and from HT-29 cells with K_i values of 3.9 and 8.6 nM, respectively. SR 48692 also antagonized the neurotensin-induced mobilization of intracellular calcium in HT-29 cells, in agreement with previous findings. In rat cerebellar slices SR 48692 blocked the increase in cyclic GMP levels evoked by neurotensin in a dose-dependent manner. In vivo, SR 48692 antagonized the increase in rat brain mesolimbic dopamine turnover induced by the systemically active neurotensin peptide, EI [(N-Me)Arg-Lys-Pro-Trp-tert-Leu-Leu]. No effects on dopamine turnover of either EI or SR 48692 were observed in the striatum. SR 48692 did not antagonize the EI-induced decreases in mouse body temperature and spontaneous locomotor activity (LMA) or the decreases in LMA induced by ICV-administered neurotensin. Although other explanations are possible, these findings support the hypothesis that a subtype of the NT receptor may mediate the locomotor and hypothermic actions of this peptide and that it is different from the NT receptor that is involved in dopamine turnover.

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Neurotensin decreases high affinity [ <sup>3</sup>H]-ouabain binding to cerebral cortex membranes
2011, Regulatory Peptides
Citation Excerpt :
Hypolocomotion induced by neurotensin is antagonized by SR 48692 [27] and it cannot be observed in deficient NTS1 receptor mice [28], indicating that NTS1 receptor is involved in this effect. However, in other studies SR 48692 failed to antagonize neurotensin induced hypolocomotion [29]. This drug fails to antagonize electrophysiological neurotensin effect on evoked current mediated by high affinity neurotensin receptor in a Xenopus oocytes expression system [30] and high affinity [3H]-ouabain binding decrease by neurotensin (present findings).
Previous work from this laboratory showed the ability of neurotensin to inhibit synaptosomal membrane Na⁺, K⁺-ATPase activity, the effect being blocked by SR 48692, a non-peptidic antagonist for high affinity neurotensin receptor (NTS1) [López Ordieres and Rodríguez de Lores Arnaiz 2000; 2001]. To further study neurotensin interaction with Na⁺, K⁺-ATPase, peptide effect on high affinity [³H]-ouabain binding was studied in cerebral cortex membranes. It was observed that neurotensin modified binding in a dose-dependent manner, leading to 80% decrease with 1 × 10^− 4 M concentration. On the other hand, the single addition of 1 × 10^− 6 M, 1 × 10^− 5 M and 1 × 10^− 4 M SR 48692 (Sanofi-Aventis, U.S., Inc.) decreased [³H]-ouabain binding (in %) to 87 ± 16; 74 ± 16 and 34 ± 17, respectively. Simultaneous addition of neurotensin and SR 48692 led to additive or synergic effects. Partial NTS2 agonist levocabastine inhibited [³H]-ouabain binding likewise. Saturation assays followed by Scatchard analyses showed that neurotensin increased K_d value whereas failed to modify B_max value, indicating a competitive type interaction of the peptide at Na⁺, K⁺-ATPase ouabain site. At variance, SR 48692 decreased B_max value whereas it did not modify K_d value. [³H]-ouabain binding was also studied in cerebral cortex membranes obtained from rats injected i. p. 30 min earlier with 100 μg and 250 μg/kg SR 48692. It was observed that the 250 μg/kg SR 48692 dose led to 19% decrease in basal [³H]-ouabain binding. After SR 48692 treatments, addition of 1 × 10^− 6 M led to additive or synergic effect. Results suggested that [³H]-ouabain binding inhibition by neurotensin hardly involves NTS1 receptor.
Effects of neurotensin in amygdaloid spatial learning mechanisms
2010, Behavioural Brain Research
Neurotensin (NT) acts as a neurotransmitter and/or neuromodulator and plays a role in learning and reward related processes. The central nucleus of amygdala (CeA) participates in the regulation of memory and learning mechanisms. In Morris water maze test, rats were microinjected with NT or neurotensin receptor-1 (NTS1) antagonist SR 48692 (ANT). NT significantly reduced the escape latency. Effect of NT was blocked by ANT pretreatment. Our results show that in the rat CeA NT facilitates spatial learning. We clarified that NTS1s are involved in this action.
The role of neurotensin in positive reinforcement in the rat central nucleus of amygdala
2010, Behavioural Brain Research
In the central nervous system neurotensin (NT) acts as a neurotransmitter and neuromodulator. It was shown that NT has positive reinforcing effects after its direct microinjection into the ventral tegmental area. The central nucleus of amygdala (CeA), part of the limbic system, plays an important role in learning, memory, regulation of feeding, anxiety and emotional behavior. By means of immunohistochemical and radioimmune methods it was shown that the amygdaloid body is relatively rich in NT immunoreactive elements and NT receptors.
The aim of our study was to examine the possible effects of NT on reinforcement and anxiety in the CeA. In conditioned place preference test male Wistar rats were microinjected bilaterally with 100 or 250 ng NT in volume of 0.4 μl or 35 ng neurotensin receptor 1 (NTS1) antagonist SR 48692 alone, or NTS1 antagonist 15 min before 100 ng NT treatment. Hundred or 250 ng NT significantly increased the time rats spent in the treatment quadrant. Prior treatment with the non-peptide NTS1 antagonist blocked the effects of NT. Antagonist itself did not influence the reinforcing effect. In elevated plus maze test we did not find differences among the groups as far as the anxiety index (time spent on the open arms) was concerned. Our results suggest that in the rat ACE NT has positive reinforcing effects. We clarified that NTS1s are involved in this action. It was also shown that NT does not influence anxiety behavior.
Bioactive analogs of neurotensin: Focus on CNS effects
2006, Peptides
Neurotensin (NT) is a 13-amino acid neuropeptide found in the central nervous system and in the gastrointestinal tract. It is closely associated anatomically with dopaminergic and other neurotransmitter systems, and evidence supports a role for NT agonists in the treatment of various neuropsychiatric disorders. However, NT is readily degraded by peptidases, so there is much interest in the development of stable NT agonists, that can be injected systemically, cross the blood–brain barrier (BBB), yet retains the pharmacological characteristics of native NT for therapeutic use in the treatment of diseases such as schizophrenia, Parkinson's disease and addiction.
Targeted inactivation of the neurotensin type 1 receptor reveals its role in body temperature control and feeding behavior but not in analgesia
2002, Brain Research
Citation Excerpt :
It was even suggested that a yet unknown NT receptor subtype might be responsible for NT-induced hypothermia [37]. Moreover, the use of the antagonist SR 48692 led to some contradictory results, since it was unable to counteract the NT-induced hypothermia in rats and mice [8,28]. The lack of effect of SR 48692 could be due to its lower affinity than NT for NT-1R rather than to its agonism of NT-2R.
Three subtypes of neurotensin receptor have been described, two members of the heptahelical transmembrane domain G protein-coupled receptor superfamily NT-1R and NT-2R, and NT-3R unrelated to this family. We have generated NT-1R deficient (NT-1R^−/−) mice. NT-1R^−/− mice were born at the expected Mendelian frequency without obvious abnormalities and they were fertile. The NT-induced analgesia on the writhing induced by phenyl-p-benzoquinone administration remained at wild-type levels in the NT-1R^−/− mice demonstrating that the NT-1R is not implicated in the analgesic effect of NT in this test. The NT-1R^−/− mice were hyperthermic; their body temperature was not affected by intracerebroventricular (i.c.v.) administration of NT, contrasting with the hypothermia induced in NT-1R^+/+ mice. NT-1R^−/− mice showed a small significant increase in body weight compared to the NT-1R^+/+ congeners as early as 10 weeks after birth, correlated with a higher food intake. NT-1R^−/− mice showed similar spontaneous locomotion to the control littermates, but did not respond to i.c.v. NT-induced hypolocomotion. I.c.v. injection of NT inhibited feeding in fasted wild-type mice, but had no effect on feeding of the NT-1R^−/− mice. I.c.v. administration of the orexigenic neuropeptide Y (NPY) stimulated feeding to the same extent in both wild-type and NT-1R^−/− mice. This analysis of NT-1R-deficient mice shows that the NT-1R does not play a role in NT-induced analgesia, but that it is clearly implicated in thermal and feeding regulation, weight control, and NT-induced hypolocomotion.
Chapter VI Neurotensin receptors in the central nervous system
2002, Handbook of Chemical Neuroanatomy
This chapter reviews the discovery of NT and briefly discusses its synthesis, degradation, distribution, and biological effects in the CNS. It focuses on the characterization and distribution of NT receptors and of their mRNA in adult and developing mammalian brain. Like many other neuropeptides, the tridecapeptide neurotensin (NT) is a messenger of intercellular communication working as a neurotransmitter or neuromodulator in the brain and as a local hormone in the periphery. Several pharmacological, morphological, and neurochemical data suggest that NT is involved in many physiological processes in the central nervous system (CNS), as well as in the gastrointestinal tract. Both central and peripheral modes of action of NT imply as a first step the recognition of the peptide by a specific receptor located on the plasma membrane of the target cell. The activated ligand-receptor complex then transduces the extracellular signal inside the cell.

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ArticleDifferential effects of the nonpeptide neurotensin antagonist, SR 48692, on the pharmacological effects of neurotensin agonists

Abstract

Neuroscience

Anal Biochem.

J. Biol. Chem.

Soc. Neurosci. Abstr.

Brain Res.

Eur. J. Pharmacol.

J. Pharmacol. Exp. Ther.

J. Pharmacol. Exp. Ther.

Naunyn Schmiedebergs Arch. Pharmacol.

Neurochem. Int.

Biorg. Med. Chem. Lett.

Neuroscience

Neuron

Neuroscience

Chem. Pharm. Bull.

Eur. J. Pharmacol. Mol. Pharmacol.

Exp. Neurol.

Neurotensin in vitro markedly reduces the affinity in subcortical limbic [3H]N-propyl-norapomorphine binding sites

Acta Physiol. Scand.

Structure-antinociceptive activity of neurotensin and some novel analogues in periaqueductal gray region of the brainstem

Brain Res.

Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum

Chem. Abst.

Article
Differential effects of the nonpeptide neurotensin antagonist, SR 48692, on the pharmacological effects of neurotensin agonists

Neurotensin in vitro markedly reduces the affinity in subcortical limbic [³H]N-propyl-norapomorphine binding sites