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William Rostène - One of the best experts on this subject based on the ideXlab platform.
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Neurotensin Receptor Antagonist administered during cocaine withdrawal decreases locomotor sensitization and conditioned place preference.
2007Co-Authors: Klara Felszeghy, William Rostène, Anne Bérod, José Espinosa, Hélène Scarna, Didier PélapratAbstract:Chronic use of psychostimulants induces enduringly increased responsiveness to a subsequent psychostimulant injection and sensitivity to drug-associated cues, contributing to drug craving and relapse. Neurotensin (NT), a neuropeptide functionally linked to dopaminergic neurons, was suggested to participate in these phenomena. We and others have reported that SR 48692, an NT Receptor Antagonist, given in pre- or co-treatments with cocaine or amphetamine, alters some behavioral effects of these drugs in rats. However, its efficacy when applied following repeated cocaine administration remains unknown. We, therefore, evaluated the ability of SR 48692, administered after a cocaine regimen, to interfere with the expression of locomotor sensitization and conditioned place preference (CPP) in rats. We demonstrated that the expression of locomotor sensitization, induced by four cocaine injections (15 mg/kg, i.p.) every other day and a cocaine challenge 1 week later, was attenuated by a subsequent 2-week daily administration of SR 48692 (1 mg/kg, i.p.). Furthermore, the expression of cocaine-induced CPP was suppressed by a 10-day SR 48692 treatment started after the conditioning period (four 15 mg/kg cocaine injections every other day). Taken together, our data show that a chronic SR 48692 treatment given after a cocaine regimen partly reverses the expression of locomotor sensitization and CPP in the rat, suggesting that NT participates in the maintenance of these behaviors. Our results support the hypothesis that targeting neuromodulatory systems, such as the NT systems may offer new strategies in the treatment of drug addiction.
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Repeated Administration of the Neurotensin Receptor Antagonist SR 48692 Differentially Regulates Mesocortical and Mesolimbic Dopaminergic Systems
2002Co-Authors: Mounia Azzi, Catalina Betancur, Inge Sillaber, Rainer Spanagel, William Rostène, Anne BérodAbstract:The purpose of the present study was to investigate the effects of repeated administration of the Neurotensin Receptor Antagonist, SR 48692, on the activity of the mesocortical and mesolimbic dopaminergic (DA) systems. We showed that daily administration of SR 48692 for 15 days (1 mg/kg i.p.) to Wistar rats increased the expression of tyrosine hydroxylase mRNA and protein in the ventral mesencephalon. Simultaneous in vivo microdialysis in the shell part of the nucleus accumbens (AcbSh) and the medial prefrontal cortex (mPFC) revealed that blockade of Neurotensin Receptors for 15 days decreased basal extracellular levels of DA (approximately 50%) and its metabolites in the AcbSh, whereas no modification in DA levels was observed in the mPFC. In animals submitted to a forced swimming stress, which preferentially enhanced extracellular DA levels in the mPFC, treatment with SR 48692 failed to affect the stress-induced increase in DA. Moreover, given that glucocorticoids can modulate the activity of mesencephalic DA neurons, we examined the effect of the same SR 48692 treatment on corticosterone levels in dialysates from the AcbSh. We found that repeated SR 48692 did not affect the basal levels of free corticosterone, but significantly reduced the increase induced by forced swimming stress. The present results demonstrate that repeated treatment with SR 48692 modulates selectively the DA mesolimbic system when compared with the mesocortical pathway. These findings suggest that long-term treatment with selective Neurotensin Receptor Antagonists could have potential clinical utility in the treatment of neuropsychiatric disorders associated with hyperactivity of the mesolimbic DA systems or the hypothalamic-pituitary-adrenal axis.
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Characterization of binding sites of a new Neurotensin Receptor Antagonist, [3H]SR 142948A, in the rat brain.
1998Co-Authors: Catalina Betancur, Danielle Gully, William Rostène, Bernard Labeeuw, Maryse Canton, Alain Burgos, Didier PélapratAbstract:The present study describes the characterization of the binding properties and autoradiographic distribution of a new nonpeptide Antagonist of Neurotensin Receptors, [3H]SR 142948A (2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methyl carbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]-amino]-ad amantane-2-carboxylic acid, hydrochloride), in the rat brain. The binding of [3H]SR 142948A in brain membrane homogenates was specific, time-dependent, reversible and saturable. [3H]SR 142948A bound to an apparently homogeneous population of sites, with a Kd of 3.5 nM and a Bmax value of 508 fmol/mg of protein, which was 80% higher than that observed in saturation experiments with [3H]Neurotensin. [3H]SR 142948A binding was inhibited by SR 142948A, the related nonpeptide Receptor Antagonist, SR 48692 (2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole -3-carbonyl]amino]-adamantane-2-carboxylic acid) and Neurotensin. Saturation and competition studies in the presence or absence of the histamine H1 Receptor Antagonist, levocabastine, revealed that [3H]SR 142948A bound with similar affinities to both the levocabastine-insensitive Neurotensin NT1 Receptors (20% of the total binding population) and the recently cloned levocabastine-sensitive Neurotensin NT2 Receptors (80% of the Receptors) (Kd = 6.8 and 4.8 nM, respectively). The regional distribution of [3H]SR 142948A binding in the rat brain closely matched the distribution of [125I]Neurotensin binding. In conclusion, these findings indicate that [3H]SR 142948A is a new potent Antagonist radioligand which recognizes with high affinity both Neurotensin NT1 and NT2 Receptors and represents thus an excellent tool to study Neurotensin Receptors in the rat brain.
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central administration of the Neurotensin Receptor Antagonist sr48692 modulates diurnal and stress related hypothalamic pituitary adrenal activity
1997Co-Authors: W Rowe, Danielle Gully, William Rostène, Arnaud Nicot, Shakti Sharma, Clairedominique Walker, Michael J Meaney, Remi QuirionAbstract:Previous studies in our laboratory suggest that Neurotensin (NT) acts centrally to modulate adrenocorticotropin hormone (ACTH) and corticosterone release. In the present studies, we examined hypothalamic-pituitary-adrenal (HPA) function under basal conditions and during restraint stress following central administration of the highly specific NT Receptor Antagonist, SR48692. Chronic delivery of SR48692 to the paraventricular nucleus (PVN) of the hypothalamus via indwelling central cannulae attenuated both the diurnal- and stress-induced elevations in HPA activity. Thus, SR48692 decreased the diurnal increase in plasma ACTH and corticosterone during the evening phase of the cycle, but did not affect morning levels. Restraint-induced increases in plasma ACTH and corticosterone levels were also significantly reduced in the SR48692-implanted animals. This suggests that the inhibitory effects of SR48692 were restricted to periods of stimulated HPA activity. A decrease in corticotropin-releasing hormone (CRH)-like immunoreactivity was observed within the PVN following chronic SR48692, and parallel decreases in CRH-like immunoreactivity were observed within the external zone of the median eminence. These findings suggest that endogenous NT serves to increase HPA activity during periods of enhanced stimulation.
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effect of the Neurotensin Receptor Antagonist sr48692 on rat blood pressure modulation by Neurotensin
1996Co-Authors: Danielle Gully, William Rostène, Le G Fur, Patrick Kitabgi, Liliane Lespy, Maryse Canton, J P MaffrandAbstract:Abstract When administered as an intravenous injection in the pentobarbitone-anaesthetized rat, Neurotensin (NT) elicits a biphasic depressor-pressor effect that can be evaluated by the mean arterial blood pressure (MABP). The first hypotensive phase elicited by low doses of NT is dependent on the interaction of NT with its specific Receptors and may be mediated by the release of histamine, since it is prevented by oral pretreatment with the selective NT Receptor Antagonist SR 48692 and by intravenous pretreatment with a selective H 1 Receptor Antagonist mepyramine. The hypertensive effect evoked by higher doses of NT is histamine-independent but remains NT Receptor-mediated. The prevention of the biphasic effect on MABP by oral administration of the NT Receptor Antagonist SR 48692 validates the implication of NT Receptors in the histamine release phenomenon.
Danielle Gully - One of the best experts on this subject based on the ideXlab platform.
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Neurotensin and a non peptide Neurotensin Receptor Antagonist control human colon cancer cell growth in cell culture and in cells xenografted into nude mice
1999Co-Authors: Jeanjose Maoret, Danielle Gully, Younes Anini, C Rouyerfessard, Marc LaburtheAbstract:The intestine is a large endocrine organ, but the dependence of colon cancer on hormones remains unknown. We show here that Neurotensin, a paracrine/endocrine peptide in the gut, and the Neurotensin Receptor Antagonist SR 48692 control colon cancer cell growth in vitro and in vivo by interacting with Receptors that are ectopically expressed in colon cancers. In cell culture, Neurotensin stimulates the growth of human colon cancer cell lines (SW480, SW620, HT29, HCT116 and Cl.19A) expressing the Neurotensin Receptor NTR1 but does not change the growth of Caco2 cells, which do not express NTR1. In SW480 cells, Neurotensin is active in the 10–10 to 10–6 M concentration range (ED50 = 0.47 nM) while the Neurotensin fragment (1–11) is inactive. Neurotensin also enhances the cellular cloning efficiency of SW480 cells in soft agar by inducing a 50% increase of colony formation. This effect is blocked by SR 48692, which alone does not alter colony formation. Subcutaneous delivery of Neurotensin (0.54μmol/kg every 24 hr) by osmotic pumps to nude mice that have been xenografted with SW480 cells results in a significant increase of tumor volume, i.e., up to 255% of control at day 20 of treatment. SR 48692 administered alone (1.7 μmol/kg every 24 hr) by daily i.p. injections reduces the development of tumors formed by xenografting SW480 cells in nude mice. A significant mean reduction of tumor volume of 38% is observed during the 22-day period of treatment. SR 48692 alone is also active at reducing tumor volume after xenografting HCT116 cells in nude mice. Our results support the notion that colon cancer growth may be dependent on blood-borne Neurotensin and suggest that non-peptide Neurotensin Antagonists, such as SR 48692, may be useful for the development of novel therapeutic strategies of colon cancer. Int. J. Cancer 80:448–454, 1999. © 1999 Wiley-Liss, Inc.
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x ray structural characterization of sr 142948 a novel potent synthetic Neurotensin Receptor Antagonist
1998Co-Authors: Luc Quere, Danielle Gully, Geraldine Longfils, Robert Boigegrain, Bernard Labeeuw, Francois DurantAbstract:SR 142948 is an original and extremely potent Neurotensin Receptor Antagonist developed in a promising approach to novel antipsychotic drugs. The X-ray structure was elucidated and compared to SR 48692 and levocabastine, providing new informations about the possible recognition process of NT Receptor subtypes.
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Characterization of binding sites of a new Neurotensin Receptor Antagonist, [3H]SR 142948A, in the rat brain.
1998Co-Authors: Catalina Betancur, Danielle Gully, William Rostène, Bernard Labeeuw, Maryse Canton, Alain Burgos, Didier PélapratAbstract:The present study describes the characterization of the binding properties and autoradiographic distribution of a new nonpeptide Antagonist of Neurotensin Receptors, [3H]SR 142948A (2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methyl carbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]-amino]-ad amantane-2-carboxylic acid, hydrochloride), in the rat brain. The binding of [3H]SR 142948A in brain membrane homogenates was specific, time-dependent, reversible and saturable. [3H]SR 142948A bound to an apparently homogeneous population of sites, with a Kd of 3.5 nM and a Bmax value of 508 fmol/mg of protein, which was 80% higher than that observed in saturation experiments with [3H]Neurotensin. [3H]SR 142948A binding was inhibited by SR 142948A, the related nonpeptide Receptor Antagonist, SR 48692 (2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole -3-carbonyl]amino]-adamantane-2-carboxylic acid) and Neurotensin. Saturation and competition studies in the presence or absence of the histamine H1 Receptor Antagonist, levocabastine, revealed that [3H]SR 142948A bound with similar affinities to both the levocabastine-insensitive Neurotensin NT1 Receptors (20% of the total binding population) and the recently cloned levocabastine-sensitive Neurotensin NT2 Receptors (80% of the Receptors) (Kd = 6.8 and 4.8 nM, respectively). The regional distribution of [3H]SR 142948A binding in the rat brain closely matched the distribution of [125I]Neurotensin binding. In conclusion, these findings indicate that [3H]SR 142948A is a new potent Antagonist radioligand which recognizes with high affinity both Neurotensin NT1 and NT2 Receptors and represents thus an excellent tool to study Neurotensin Receptors in the rat brain.
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central administration of the Neurotensin Receptor Antagonist sr48692 modulates diurnal and stress related hypothalamic pituitary adrenal activity
1997Co-Authors: W Rowe, Danielle Gully, William Rostène, Arnaud Nicot, Shakti Sharma, Clairedominique Walker, Michael J Meaney, Remi QuirionAbstract:Previous studies in our laboratory suggest that Neurotensin (NT) acts centrally to modulate adrenocorticotropin hormone (ACTH) and corticosterone release. In the present studies, we examined hypothalamic-pituitary-adrenal (HPA) function under basal conditions and during restraint stress following central administration of the highly specific NT Receptor Antagonist, SR48692. Chronic delivery of SR48692 to the paraventricular nucleus (PVN) of the hypothalamus via indwelling central cannulae attenuated both the diurnal- and stress-induced elevations in HPA activity. Thus, SR48692 decreased the diurnal increase in plasma ACTH and corticosterone during the evening phase of the cycle, but did not affect morning levels. Restraint-induced increases in plasma ACTH and corticosterone levels were also significantly reduced in the SR48692-implanted animals. This suggests that the inhibitory effects of SR48692 were restricted to periods of stimulated HPA activity. A decrease in corticotropin-releasing hormone (CRH)-like immunoreactivity was observed within the PVN following chronic SR48692, and parallel decreases in CRH-like immunoreactivity were observed within the external zone of the median eminence. These findings suggest that endogenous NT serves to increase HPA activity during periods of enhanced stimulation.
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inhibition of Neurotensin induced pancreatic carcinoma growth by a nonpeptide Neurotensin Receptor Antagonist sr48692
1997Co-Authors: M Kazuhiro D Iwase, Danielle Gully, Mark B Evers, Mark R Hellmich, M Hong Jin D Kim, M Shunichi D Higashide, C James M D Thompson, M Courtney M D TownsendAbstract:BACKGROUND Recently, a nonpeptide Neurotensin (NT) Receptor Antagonist, SR48692, was developed that selectively antagonizes the high affinity, biologically active NT binding site. The effect of SR48692 on NT-mediated growth of a human pancreatic carcinoma, MIA PaCa-2, was determined both in vitro and in vivo. METHODS 125I-NT binding and Northern blot analyses were performed for evaluation of the NT Receptor in MIA PaCa-2 cells. Intracellular calcium ([Ca2+]i) mobilization and inositol phosphate (IP3) levels were measured. Cell growth studies were performed by counting cell numbers. Athymic nude mice were inoculated with MIA PaCa-2 cells and randomized into four groups to receive either vehicle (NT or SR48692) or NT + SR48692. RESULTS MIA PaCa-2 cells possess both a high affinity, SR48692-sensitive and a levocabastine-insensitive NT binding site; Northern blot analysis demonstrated expression of the NT Receptor. SR48692 inhibited [Ca2+]i mobilization, IP3 turnover, and MIA PaCa-2 cell growth induced by NT in a dose-dependent fashion. In in vivo experiments, NT significantly increased the size, weight, and DNA and protein content of xenografted MIA PaCa-2 tumors; SR48692 inhibited the effect of NT. CONCLUSIONS The novel NT Receptor Antagonist SR48692 will be a valuable agent to delineate further the cellular mechanisms responsible for peptide-mediated growth of normal and neoplastic gut tissues. Cancer 1997; 79:1787-93. © 1997 American Cancer Society.
Didier Pélaprat - One of the best experts on this subject based on the ideXlab platform.
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Neurotensin Receptor Antagonist administered during cocaine withdrawal decreases locomotor sensitization and conditioned place preference.
2007Co-Authors: Klara Felszeghy, William Rostène, Anne Bérod, José Espinosa, Hélène Scarna, Didier PélapratAbstract:Chronic use of psychostimulants induces enduringly increased responsiveness to a subsequent psychostimulant injection and sensitivity to drug-associated cues, contributing to drug craving and relapse. Neurotensin (NT), a neuropeptide functionally linked to dopaminergic neurons, was suggested to participate in these phenomena. We and others have reported that SR 48692, an NT Receptor Antagonist, given in pre- or co-treatments with cocaine or amphetamine, alters some behavioral effects of these drugs in rats. However, its efficacy when applied following repeated cocaine administration remains unknown. We, therefore, evaluated the ability of SR 48692, administered after a cocaine regimen, to interfere with the expression of locomotor sensitization and conditioned place preference (CPP) in rats. We demonstrated that the expression of locomotor sensitization, induced by four cocaine injections (15 mg/kg, i.p.) every other day and a cocaine challenge 1 week later, was attenuated by a subsequent 2-week daily administration of SR 48692 (1 mg/kg, i.p.). Furthermore, the expression of cocaine-induced CPP was suppressed by a 10-day SR 48692 treatment started after the conditioning period (four 15 mg/kg cocaine injections every other day). Taken together, our data show that a chronic SR 48692 treatment given after a cocaine regimen partly reverses the expression of locomotor sensitization and CPP in the rat, suggesting that NT participates in the maintenance of these behaviors. Our results support the hypothesis that targeting neuromodulatory systems, such as the NT systems may offer new strategies in the treatment of drug addiction.
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Characterization of binding sites of a new Neurotensin Receptor Antagonist, [3H]SR 142948A, in the rat brain.
1998Co-Authors: Catalina Betancur, Danielle Gully, William Rostène, Bernard Labeeuw, Maryse Canton, Alain Burgos, Didier PélapratAbstract:The present study describes the characterization of the binding properties and autoradiographic distribution of a new nonpeptide Antagonist of Neurotensin Receptors, [3H]SR 142948A (2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methyl carbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]-amino]-ad amantane-2-carboxylic acid, hydrochloride), in the rat brain. The binding of [3H]SR 142948A in brain membrane homogenates was specific, time-dependent, reversible and saturable. [3H]SR 142948A bound to an apparently homogeneous population of sites, with a Kd of 3.5 nM and a Bmax value of 508 fmol/mg of protein, which was 80% higher than that observed in saturation experiments with [3H]Neurotensin. [3H]SR 142948A binding was inhibited by SR 142948A, the related nonpeptide Receptor Antagonist, SR 48692 (2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole -3-carbonyl]amino]-adamantane-2-carboxylic acid) and Neurotensin. Saturation and competition studies in the presence or absence of the histamine H1 Receptor Antagonist, levocabastine, revealed that [3H]SR 142948A bound with similar affinities to both the levocabastine-insensitive Neurotensin NT1 Receptors (20% of the total binding population) and the recently cloned levocabastine-sensitive Neurotensin NT2 Receptors (80% of the Receptors) (Kd = 6.8 and 4.8 nM, respectively). The regional distribution of [3H]SR 142948A binding in the rat brain closely matched the distribution of [125I]Neurotensin binding. In conclusion, these findings indicate that [3H]SR 142948A is a new potent Antagonist radioligand which recognizes with high affinity both Neurotensin NT1 and NT2 Receptors and represents thus an excellent tool to study Neurotensin Receptors in the rat brain.
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Characterization and distribution of binding sites for a new Neurotensin Receptor Antagonist ligand, [3H]SR 48692, in the guinea pig brain.
1995Co-Authors: Catalina Betancur, Danielle Gully, Didier Pélaprat, Maryse Canton, Gema Vela, William RostèneAbstract:SR 48692, a selective nonpeptide Antagonist of Neurotensin (NT) Receptors was developed recently. In the present work we studied the binding properties of the corresponding radioligand, [3H]SR 48692, in the adult guinea pig brain. The characterization of [3H]SR 48692 binding was carried out on brain membrane preparations and the distribution of [3H]SR 48692 binding sites was determined by Receptor autoradiography and compared to that of [125I]NT binding sites. In brain homogenates, [3H]SR 48692 bound to a single population of sites with a Kd of 2.19 nM and a maximal binding capacity of 1.15 pmol/mg of protein. This maximal binding capacity value was 20 times higher than that observed for [125I]NT. NT agonists were able to interact competitively with the entire population of binding sites labeled by [3H]SR 48692, but their affinities were much lower than those observed for [125I]NT. By contrast, NT Antagonists exhibited similar abilities to inhibit the binding of both radioligands. The addition of unlabeled NT in saturation assays revealed a competitive inhibition of [3H]SR 48692 binding, suggesting that agonist and Antagonist ligand bind to overlapping domains of the NT Receptor. The autoradiographic distribution of the low-affinity NT binding sites detected by [3H]SR 48692 (96% of the Receptors) was very similar to the distribution of high-affinity Receptors labeled with [125I]NT (4% of the Receptors). In addition, the binding of [3H]SR 48692 was insensitive to guanyl nucleotides. Taken together, these findings suggest that the binding sites detected by [3H]SR 48692 in the guinea pig brain mainly represent the uncoupled form of the NT Receptor.
Catalina Betancur - One of the best experts on this subject based on the ideXlab platform.
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Repeated Administration of the Neurotensin Receptor Antagonist SR 48692 Differentially Regulates Mesocortical and Mesolimbic Dopaminergic Systems
2002Co-Authors: Mounia Azzi, Catalina Betancur, Inge Sillaber, Rainer Spanagel, William Rostène, Anne BérodAbstract:The purpose of the present study was to investigate the effects of repeated administration of the Neurotensin Receptor Antagonist, SR 48692, on the activity of the mesocortical and mesolimbic dopaminergic (DA) systems. We showed that daily administration of SR 48692 for 15 days (1 mg/kg i.p.) to Wistar rats increased the expression of tyrosine hydroxylase mRNA and protein in the ventral mesencephalon. Simultaneous in vivo microdialysis in the shell part of the nucleus accumbens (AcbSh) and the medial prefrontal cortex (mPFC) revealed that blockade of Neurotensin Receptors for 15 days decreased basal extracellular levels of DA (approximately 50%) and its metabolites in the AcbSh, whereas no modification in DA levels was observed in the mPFC. In animals submitted to a forced swimming stress, which preferentially enhanced extracellular DA levels in the mPFC, treatment with SR 48692 failed to affect the stress-induced increase in DA. Moreover, given that glucocorticoids can modulate the activity of mesencephalic DA neurons, we examined the effect of the same SR 48692 treatment on corticosterone levels in dialysates from the AcbSh. We found that repeated SR 48692 did not affect the basal levels of free corticosterone, but significantly reduced the increase induced by forced swimming stress. The present results demonstrate that repeated treatment with SR 48692 modulates selectively the DA mesolimbic system when compared with the mesocortical pathway. These findings suggest that long-term treatment with selective Neurotensin Receptor Antagonists could have potential clinical utility in the treatment of neuropsychiatric disorders associated with hyperactivity of the mesolimbic DA systems or the hypothalamic-pituitary-adrenal axis.
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Characterization of binding sites of a new Neurotensin Receptor Antagonist, [3H]SR 142948A, in the rat brain.
1998Co-Authors: Catalina Betancur, Danielle Gully, William Rostène, Bernard Labeeuw, Maryse Canton, Alain Burgos, Didier PélapratAbstract:The present study describes the characterization of the binding properties and autoradiographic distribution of a new nonpeptide Antagonist of Neurotensin Receptors, [3H]SR 142948A (2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methyl carbamoyl)-2-isopropylphenyl)-1H-pyrazole-3-carbonyl]-amino]-ad amantane-2-carboxylic acid, hydrochloride), in the rat brain. The binding of [3H]SR 142948A in brain membrane homogenates was specific, time-dependent, reversible and saturable. [3H]SR 142948A bound to an apparently homogeneous population of sites, with a Kd of 3.5 nM and a Bmax value of 508 fmol/mg of protein, which was 80% higher than that observed in saturation experiments with [3H]Neurotensin. [3H]SR 142948A binding was inhibited by SR 142948A, the related nonpeptide Receptor Antagonist, SR 48692 (2-[[1-(7-chloroquinolin-4-yl)-5-(2,6-dimethoxyphenyl)-1H-pyrazole -3-carbonyl]amino]-adamantane-2-carboxylic acid) and Neurotensin. Saturation and competition studies in the presence or absence of the histamine H1 Receptor Antagonist, levocabastine, revealed that [3H]SR 142948A bound with similar affinities to both the levocabastine-insensitive Neurotensin NT1 Receptors (20% of the total binding population) and the recently cloned levocabastine-sensitive Neurotensin NT2 Receptors (80% of the Receptors) (Kd = 6.8 and 4.8 nM, respectively). The regional distribution of [3H]SR 142948A binding in the rat brain closely matched the distribution of [125I]Neurotensin binding. In conclusion, these findings indicate that [3H]SR 142948A is a new potent Antagonist radioligand which recognizes with high affinity both Neurotensin NT1 and NT2 Receptors and represents thus an excellent tool to study Neurotensin Receptors in the rat brain.
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Characterization and distribution of binding sites for a new Neurotensin Receptor Antagonist ligand, [3H]SR 48692, in the guinea pig brain.
1995Co-Authors: Catalina Betancur, Danielle Gully, Didier Pélaprat, Maryse Canton, Gema Vela, William RostèneAbstract:SR 48692, a selective nonpeptide Antagonist of Neurotensin (NT) Receptors was developed recently. In the present work we studied the binding properties of the corresponding radioligand, [3H]SR 48692, in the adult guinea pig brain. The characterization of [3H]SR 48692 binding was carried out on brain membrane preparations and the distribution of [3H]SR 48692 binding sites was determined by Receptor autoradiography and compared to that of [125I]NT binding sites. In brain homogenates, [3H]SR 48692 bound to a single population of sites with a Kd of 2.19 nM and a maximal binding capacity of 1.15 pmol/mg of protein. This maximal binding capacity value was 20 times higher than that observed for [125I]NT. NT agonists were able to interact competitively with the entire population of binding sites labeled by [3H]SR 48692, but their affinities were much lower than those observed for [125I]NT. By contrast, NT Antagonists exhibited similar abilities to inhibit the binding of both radioligands. The addition of unlabeled NT in saturation assays revealed a competitive inhibition of [3H]SR 48692 binding, suggesting that agonist and Antagonist ligand bind to overlapping domains of the NT Receptor. The autoradiographic distribution of the low-affinity NT binding sites detected by [3H]SR 48692 (96% of the Receptors) was very similar to the distribution of high-affinity Receptors labeled with [125I]NT (4% of the Receptors). In addition, the binding of [3H]SR 48692 was insensitive to guanyl nucleotides. Taken together, these findings suggest that the binding sites detected by [3H]SR 48692 in the guinea pig brain mainly represent the uncoupled form of the NT Receptor.
Georgina Rodríguez De Lores Arnaiz - One of the best experts on this subject based on the ideXlab platform.
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The low affinity Neurotensin Receptor Antagonist levocabastine impairs brain nitric oxide synthesis and mitochondrial function by independent mechanisms.
2017Co-Authors: Silvia Lores-arnaiz, Analía G. Karadayian, Alicia Gutnisky, Georgina Rodríguez De Lores ArnaizAbstract:Neurotensin is known to inhibit neuronal Na+ , K+ -ATPase, an effect that is rescued by nitric oxide (NO) synthase inhibition. However, whether the Neurotensinergic and the nitrergic systems are independent pathways, or are mechanistically linked, remains unknown. Here, we addressed this issue and found that the administration of low affinity Neurotensin Receptor (NTS2) Antagonist, levocabastine (50 μg/kg, i.p.) inhibited NO synthase (NOS) activity by 74 and 42% after 18 h in synaptosomal and mitochondrial fractions isolated from the Wistar rat cerebral cortex, respectively; these effects disappeared 36 h after levocabastine treatment. Intriguingly, whereas neuronal NOS protein abundance decreased (by 56%) in synaptosomes membranes, it was enhanced (by 86%) in mitochondria 18 h after levocabastine administration. Levocabastine enhanced the respiratory rate of synaptosomes in the presence of oligomycin, but it failed to alter the spare respiratory capacity; furthermore, the mitochondrial respiratory chain (MRC) complexes I-IV activities were severely diminished by levocabastine administration. The inhibition of NOS and MRC complexes activities were also observed after incubation of synaptosomes and mitochondria with levocabastine (1 μM) in vitro. These data indicate that the NTS2 Antagonist levocabastine regulates NOS expression and activity at the synapse, suggesting an interrelationship between the Neurotensinergic and the nitrergic systems. However, the bioenergetics effects of NTS2 activity inhibition are likely to be independent from the regulation of NO synthesis.