Effects of a novel neurotensin peptide analog given extracranially on CNS behaviors mediated by apomorphine and haloperidol

Cusack, Bernadette; Boules, Mona; Tyler, Beth M.; Fauq, Abdul H.; McCormick, Daniel J.; Richelson, Elliott

doi:10.1016/s0006-8993(99)02363-x

Cited by 72 publications

(42 citation statements)

References 36 publications

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“…NT, the peripheral administration of the metabolically stable, brain-penetrant NT analog NT-2 (Machida et al, 1993;Banks et al, 1995) to wild-type mice also caused hypothermia, hot-plate analgesia, and reduced rotarod performance in vivo, but again these effects were absent in the NTR1 knockout mice. These results substantiate the importance of NTR1 in these activities and confirm the utility of these brain-penetrant NT analogs in studying the CNS actions of NT (Pugsley et al, 1995;Sarhan et al, 1997;Tyler et al, 1999;Cusack et al, 2000;Tyler-McMahon et al, 2000).…”

Section: Ntr1 Knockout Mice 311supporting

confidence: 78%

“…Upon central administration, NT and NT agonist analogs have been shown over the years to produce a constellation of effects in rodents, including hypothermia, analgesia, sedation, and antipsychotic-like activity (Bissette et al, 1976;Nemeroff et al, 1977;Clineschmidt et al, 1979;Nemeroff, 1980;Kinkead et al, 1999;Cusack et al, 2000). Most, if not all, of these CNS effects of NT can be mimicked by systemic dosing of metabolically stable analogs of NT, most notably NT-2 (Machida et al, 1993;Sarhan et al, 1997) and NT69L (Cusack et al, 2000;Tyler-McMahon et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…Most, if not all, of these CNS effects of NT can be mimicked by systemic dosing of metabolically stable analogs of NT, most notably NT-2 (Machida et al, 1993;Sarhan et al, 1997) and NT69L (Cusack et al, 2000;Tyler-McMahon et al, 2000). NT is also known for its pharmacological effects on certain peripheral functions, including effects on intestinal motor and secretory activity (Kitabgi and Freychet, 1978), as well as certain ef- fects on endocrine and neuroendocrine function (Brown and Miller, 1982).…”

Section: Discussionmentioning

confidence: 99%

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

Pettibone

Hess²,

Hey³

et al. 2002

J Pharmacol Exp Ther

121

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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 (Ϫ/Ϫ) mice were viable, and showed normal growth and overt behavior. The Ϫ/Ϫ mice lacked detectable NTR1 radioligand binding in brain, whereas NTR2 receptor binding density appeared normal compared with wildtype (ϩ/ϩ) 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 g) to ϩ/ϩ mice caused a robust hypothermic response (5-6°C) and a significant increase in hot-plate latency. These effects were absent in the Ϫ/Ϫ mice. Similar results were obtained with i.p. injections of the brainpenetrant 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 ϩ/ϩ mice, but no responses were observed with tissues from Ϫ/Ϫ 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.

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Section: Ntr1 Knockout Mice 311supporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Pettibone

Hess²,

Hey³

et al. 2002

J Pharmacol Exp Ther

121

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“…Furthermore, haloperidol-induced catalepsy was unaffected in NT knockout mice [35], and NT antagonist treatment potentiated haloperidol-induced catalepsy at suboptimal doses of haloperidol, indicating that NT opposes catalepsy [124]. Consistent with this idea, peripheral administration of a stable NT analog, NT69L, has been shown to block or reverse haloperidol-induced catalepsy in rats [125]. In contrast, SR 48692 microinjection into the striatum, pallidum or substantia nigra attenuated chronic fluphenazine-induced vacuous chewing movements [121].…”

mentioning

confidence: 79%

Multitasking with neurotensin in the central nervous system

Dobner

2005

Cell. Mol. Life Sci.

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The 13-amino acid peptide neurotensin (NT) was discovered over 30 years ago and has been implicated in a wide variety of neurotransmitter and endocrine functions. This review focuses on four areas where there has been substantial recent progress in understanding NT signaling and several functions of the endogenous peptide. The first area concerns the functional activation of the high-affinity NT receptor, NTR-1, including the delineation of the NT binding pocket and receptor domains involved in functional coupling to intracellular signaling pathways. The development of NT receptor antagonists and the application of genetic and molecular genetic approaches have accelerated progress in understanding NT function in several areas, including the involvement of NT in antipsychotic drug actions, psychostimulant sensitization and the modulation of pain, and these are reviewed in that order. There is now substantial evidence indicating that NT is required for certain antipsychotic drug actions and that the peptide plays a key role in stress-induced analgesia.

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“…NT69L also functions as an atypical antipsychotic and has nocioceptive properties, but other therapeutic properties or side effects have not yet been identified. 33 …”

mentioning

confidence: 99%

Untitled

2001

Academic Emergency Medicine

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Abstract. Objective: To determine whether the neurotensin analog NT69L, administered systemically, could induce mild brain hypothermia after asphyxial cardiac arrest (ACA) in rats. Methods: The study design was experimental, blinded, randomized, and approved by the animal use committee. All rats had continuous monitoring of brain temperature and sustained 8 minutes of ACA, resuscitation, and either saline or NT69L intravenously after return of spontaneous circulation (ROSC). Rats surviving 14 days after ACA had a neurological deficit score (NDS) and a Morris Water Maze (MWM) test. Results: Seven of eight rats in each group survived 14 days. Brain temperature was less than 35ЊC 13.1 Ϯ 3 minutes (meanϮ standard deviation) after NT69L vs controls that remained 37.5ЊC at the same ambient temperature (p < 0.05 ANOVA). The NT69L group remained below 35ЊC for 300 Ϯ 100 minutes while the controls remained at 37.5 Ϯ 0.5ЊC. The NDS in the NT69L rats was 3 Ϯ 3% vs controls 26 Ϯ 8% (p < 0.05, Kruskal-Wallis, 0% = normal, 100% = brain dead). The NT69L rats performed better on the MWM vs the controls (22 Ϯ 8 sec vs 45 Ϯ 26 sec, respectively, p < 0.05 ANOVA). Conclusions: NT69L induced rapid and prolonged mild brain hypothermia after ACA in this rat model and reduced neurological deficits.

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Effects of a novel neurotensin peptide analog given extracranially on CNS behaviors mediated by apomorphine and haloperidol

Cited by 72 publications

References 36 publications

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

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

Multitasking with neurotensin in the central nervous system

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