SR 48692-sensitive neurotensin receptors modulate acetylcholine release in the rat striatum

doi:10.1016/0143-4179(95)90053-5

Neuropeptides

Volume 29, Issue 1, July 1995, Pages 27-31

https://doi.org/10.1016/0143-4179(95)90053-5 Get rights and content

Abstract

The effects of stimulation and blockade of neurotensin receptors on striatal acetylcholine release were examined in anaesthetized rats using microdialysis. Local perfusion with neurotensin (100 nM) did not influence the release of acetylcholine. Application of neurotensin (100 nM) 30 min after haloperidol (125 μg/kg, i.p.) increased acetylcholine levels to 188% compared to 120% when haloperidol was administered alone. SR 48692 (3–100 μg/kg, i.p.) dose-dependently reduced the stimulatory effect of neurotensin in the presence of haloperidol. Comparable antagonism was observed with SR 48527, a chemically-related compound with high affinity for neurotensin receptors, but not with SR 49711, its low-affinity antipode. These results indicate that high affinity neurotensin receptors regulate acetylcholine release, when D₂-dopaminergic inhibitory input is suppressed.

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Cited by (15)

Evidence for a role of endogenous neurotensin in the development of sensitization to the locomotor stimulant effect of morphine
2008, European Journal of Pharmacology
This experiment was aimed at exploring the role of endogenous neurotensin in the development of sensitization to the locomotor stimulant effect of morphine. During the induction phase (Days 1, 3, 5 and 7), male Long–Evans adult rats were treated with the neurotensin antagonist SR-48692 (160, 320 or 640 µg/kg, i.p.) or its vehicle, followed by morphine (5.0 mg/kg, i.p.) or its vehicle, and their locomotor activity (ambulatory, non-ambulatory and vertical activity) was measured for 2 h. One week after the last injection, each group received a single injection of morphine (2.5 mg/kg, i.p.) and their locomotor activity was again measured for 2 h (sensitization test, day 14). Results show that SR-48692 alone did not change locomotion. Morphine stimulated locomotor activity, an effect that was stronger on day 7 than on day 1. The two higher doses of SR-48692 attenuated the acute stimulant effect of morphine and prevented the observed increase from day 1 to day 7. The sensitization test on day 14 showed that rats pre-treated with morphine alone displayed significantly stronger ambulatory and vertical activity than vehicle pre-treated rats, a sensitization effect that was attenuated by SR-48692. The present results suggest that endogenous neurotensin contributes to the acute locomotor stimulant effect of morphine and to the induction of its sensitization.
Neurotensin modulation of acetylcholine, GABA, and aspartate release from rat prefrontal cortex studied in vivo with microdialysis
2008, Brain Research Bulletin
The effects of the peptide transmitter neurotensin (NT) on the release of acetylcholine (ACh), γ-aminobutyric acid (GABA), glutamate (Glu), aspartate (Asp), and taurine from the prefrontal cortex (PFC) of freely moving rats were studied by transversal microdialysis. Neurotensin (0.2 and 1 μM) administered locally in the PFC produced a concentration-dependent increase in the extracellular levels of ACh, GABA, and Asp, but not of Glu or taurine. The increase produced by 1 μM NT reached a maximum of about 240% for ACh, 370% for GABA, and 380% for Asp. Lower doses of NT (0.05 μM) did not cause a significant change in ACh, GABA, or Asp output in the PFC. Higher concentrations of NT (2 μM) did not induce further increases in the level of neurotransmitters. A high-affinity selective neurotensin receptor (NTR1) antagonist SR 48692 (0.5 μM) perfused locally blocked neurotensin (1 μM)-evoked ACh, GABA, and Asp release. Local infusion of the sodium channel blocker tetrodotoxin (TTX) (1 μM) decreased the release of ACh, had no significant effect on GABA or Asp release, and prevented the 1 μM neurotensin-induced increase in ACh, GABA, and Asp output. Removal of calcium from the Ringer's solution prevented the peptide from having any effects on the neurotransmitters. Thus, in vivo NT plays a modulatory role in the PFC by interacting with cortical neurons releasing GABA and Asp and with ACh-containing neurons projecting to the PFC. The NT effects are of neural origin, as they are TTX-sensitive, and mediated by the NTR1 receptor, as they are antagonized by SR 48692.
Chronic blockade of neurotensin receptors strongly reduces sensitized, but not acute, behavioral response to D-amphetamine
2002, Neuropsychopharmacology
This study investigated the effect of a chronic blockade of neurotensin (NT) receptors on the sensitized behavioral response to amphetamine using a nonpeptide NT receptor antagonist, SR 48692. Rats received four injections of D-amphetamine (0.5 or 1 mg/kg, IP) every other day (day 1, 3, 5 and 7) and were then challenged with the same dose of amphetamine after a 6-day withdrawal (day 14) to establish the presence of locomotor sensitization. Daily administration of SR 48692 (1 mg/kg, IP) throughout the amphetamine regimen (day 1 to day 14) almost completely blocked the sensitized locomotor response to amphetamine without affecting stereotyped behaviors (experiment 1). The decreased amphetamine-induced sensitization in chronically SR 48692-treated rats did not appear to result from an influence on basal locomotor activity, as chronic SR 48692 treatment did not modify the spontaneous locomotor activity developed in response to mild stresses (experiment 2). Moreover, we showed that chronic pretreatment with SR 48692 (1 mg/kg, 14 daily IP injections) had no effect on the locomotor activation induced by a single IP administration of amphetamine (experiment 3). These data suggest that a sustained blockade of NT receptors considerably reduces the sensitized behavioral response to amphetamine without altering the acute effect of this psychostimulant or the locomotor activation induced by a mild stress. This ability of SR 48692 to specifically reduce the behavioral sensitization to amphetamine suggests that NT receptor antagonists could have potential clinical utility in the treatment of some psychiatric disorders.
Evidence for a role of endogenous neurotensin in the initiation of amphetamine sensitization
2000, Neuropharmacology
This study was aimed at testing the hypothesis that endogenous neurotensin plays a role in the initiation of sensitization to the locomotor activating effect of amphetamine. During an initial training phase, different groups of male rats were injected on four occasions (every second day: Days 1, 3, 5 and 7) with one of three doses (40, 80 or 160 μg/kg, ip) of the neurotensin antagonist, SR-48692, or its vehicle, followed 30 min later by amphetamine (1.5 mg/kg, ip), or saline. Ambulatory, non-ambulatory, and vertical movements were measured for 2 h in photocell cages immediately following the second injection. One week after the training phase, sensitivity to amphetamine (0.75 mg/kg, ip) was tested in all the rats (sensitization test). The results show that SR-48692, when given alone, produced levels of locomotor activity that were not statistically different from control. At the low dose, it potentiated amphetamine-induced ambulatory and non-ambulatory movements, an effect observed on Day 7 but not on Day 1. On the day of the sensitization test, rats pre-exposed to amphetamine alone displayed stronger ambulatory and non-ambulatory movements than vehicle pre-exposed rats, a sensitization effect that was attenuated and prevented by SR-48692 at 80 and 160 μg/kg, respectively. The present results demonstrate that activation of neurotensin receptors by endogenous neurotensin is required for the initiation of amphetamine sensitization. They provide additional evidence that an increase in central neurotensinergic neurotransmission may lead to a lasting increased sensitivity to psychostimulant drugs.
Comparative effects of neurotensin, neurotensin(8-13) and [D- Tyr<sup>11</sup>]neurotensin applied into the ventral tegmental area on extracellular dopamine in the rat prefrontal cortex and nucleus accumbens
2000, Neuroscience
Ejections of 10⁻⁵–10⁻³ M neurotensin into the ventral tegmental area increased dopamine efflux measured by electrochemical approaches in the prefrontal cortex of anaesthetized rats. In the same conditions, the effects evoked on dopamine efflux by 10⁻⁵ M neurotensin(8-13) and [D-Tyr¹¹]neurotensin were different from each other and depended on the explored area: the prefrontal cortex and the caudal and rostral nucleus accumbens. In the prefrontal cortex, neurotensin(8-13) was as potent as neurotensin, whereas [D-Tyr¹¹]neurotensin was ineffective. In the caudal nucleus accumbens, when considering the initial intensity of the effect, neurotensin(8-13) and neurotensin appeared more potent than [D-Tyr¹¹]neurotensin. In contrast, in the rostral nucleus accumbens, neurotensin(8-13) was less potent than [D-Tyr¹¹]neurotensin and neurotensin.
These results support the differential involvement of two pharmacologically distinct neurotensin receptor entities on ventral tegmental area neurons in the modulation of mesolimbic and mesocortical dopaminergic activity.
Neurotensin-SPDP-poly-L-lysine conjugate: A nonviral vector for targeted gene delivery to neural cells
1999, Molecular Brain Research
We report herein the synthesis of a novel DNA delivery system and in vitro evidence of its ability to transfect cell lines by binding to the high-affinity neurotensin receptor and subsequent internalization of ligand-receptor complexes. The targeting vehicle consisted of neurotensin crosslinked with poly-l-lysine via N-succinimidyl-3-(2-pyridyldithio) propionate (SPDP). The SPDP-derivatives with either neurotensin or poly-l-lysine were purified by gel filtration. The conjugate resulting of the reaction of neurotensin-SPDP with HS-SPDP-poly-l-lysine was purified through Biogel A 1.5. The neurotensin-SPDP-poly-l-lysine conjugate was able to bind plasmidic DNAs (pSV2cat and pGreen Lantern-1) at optimal molar ratios of 1:5 and 1:6 (DNA: conjugate), respectively. The conjugate internalized those plasmids in the cell lines (N1E-115 and HT-29) bearing the high-affinity neurotensin receptor. Expression of the plasmid products, chloramphenicol acetyltransferase and green fluorescent protein, was observed in such cell lines. Both internalization and expression of the plasmids transferred by the neurotensin-SPDP-poly-l-lysine conjugate were prevented by neurotensin (1 μM) and SR-48692 (100 nM), a specific antagonist of the high-affinity neurotensin receptor. The neurotensin-SPDP-poly-l-lysine conjugate was unable to transfect cell lines lacking the neurotensin receptor (COS-7 and L-929). In rat brain, the high-affinity neurotensin receptor is expressed by specific neurons such as those of the nigrostriatal and mesolimbic dopaminergic systems. Therefore, the neurotensin-SPDP-poly-l-lysine conjugate could be a useful tool for gene delivery to those neuronal systems.

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SR 48692-sensitive neurotensin receptors modulate acetylcholine release in the rat striatum

Abstract

J. Biol. Chem.

Brain Res. Rev.

Neurosci. Lett.

Brain Res.

Brain Res.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neuropeptides

Neuroscience

Origin of the neurotensinergic innervation of the cholinergic basal forebrain in the rat determined by retrograde transport and double immunohistochemistry

Soc. Neurosci. Abstr.