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Maurizio Massi - One of the best experts on this subject based on the ideXlab platform.
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Reversal of Stress- and CRF-induced anorexia in rats by the synthetic nociceptin/orphanin FQ receptor agonist, Ro 64-6198.
Psychopharmacology, 2002Co-Authors: Roberto Ciccocioppo, Michela Biondini, Lorena Antonelli, Juergen Wichmann, Francois Jenck, Maurizio MassiAbstract:Rationale: (1S,3aS)-8-(2,3,3,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198), a non-peptidic agonist for the opioid receptor-like1 (ORL1) receptor, exhibits anxiolytic properties in Stressful conditions. Objective: The present study was aimed at evaluating whether activation of ORL1 receptors by Ro 64-6198 may reverse the anorectic effect of restraint Stress or intracerebroventricular (ICV) CRF injection. Methods: In body restraint experiments, 20-h food deprived rats were treated with intraperitoneal (IP) injection of Ro 64-6198 or vehicle. Ten minutes later, they were confined in cylindrical Plexiglas tubes for 60 min and then returned to their cage with food. In CRF experiments, 20-h food deprived rats were IP injected with Ro 64-6198 or vehicle. Ten minutes later, they received ICV CRF, 200 ng/rat or vehicle; food was offered after 20 min. Results: Intraperitoneal (IP) pretreatment with Ro 64-6198 reversed the hypophagic effect induced by both restraint or CRF; the effect was statistically significant at the three doses tested (0.3, 1.0 or 2.5 mg/kg). ICV administration of the selective ORL1 receptor antagonist [Nphe1]NC(1–13)NH2 (two injections of 33 or 66 µg/rat) abolished the effect of Ro 64-6198 on CRF-induced anorexia. In freely feeding rats, Ro 64-6198 significantly increased feeding at 2.5, but not at 0.3 or 1.0 mg/kg; in food deprived rats, Ro 64-6198 (0.3 or 1.0 mg/kg) did not modify food intake. Thus, Reversal of Stress- and CRF-induced anorexia by Ro 64-6198 can be evoked at doses lower than those that are hyperphagic. Ro 64-6198 (1 or 2.5 mg/kg) did not modify the anorectic effect of E. coli lipopolysaccharide, suggesting that its effect is selective for Stress- or CRF-induced anorexia. Lastly, the benzodiazepine diazepam was unable to reduce the anorectic effect of CRF at the anxiolytic dose of 0.3 mg/kg, and partially reduced it at the hyperphagic dose of 1 mg/kg. Conclusions: The results of this study show that the non-peptidic ORL1 receptor agonist Ro 64-6198 markedly and selectively inhibits the anorectic effect of Stress and CRF, and provide evidence that this effect is mediated by ORL1 receptors. Thus, Ro 64-6198 may represent an interesting tool for treatment of Stress-induced anorexia.
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Reversal of Stress and crf induced anorexia in rats by the synthetic nociceptin orphanin fq receptor agonist ro 64 6198
Psychopharmacology, 2002Co-Authors: Roberto Ciccocioppo, Michela Biondini, Lorena Antonelli, Juergen Wichmann, Francois Jenck, Maurizio MassiAbstract:Rationale: (1S,3aS)-8-(2,3,3,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198), a non-peptidic agonist for the opioid receptor-like1 (ORL1) receptor, exhibits anxiolytic properties in Stressful conditions. Objective: The present study was aimed at evaluating whether activation of ORL1 receptors by Ro 64-6198 may reverse the anorectic effect of restraint Stress or intracerebroventricular (ICV) CRF injection. Methods: In body restraint experiments, 20-h food deprived rats were treated with intraperitoneal (IP) injection of Ro 64-6198 or vehicle. Ten minutes later, they were confined in cylindrical Plexiglas tubes for 60 min and then returned to their cage with food. In CRF experiments, 20-h food deprived rats were IP injected with Ro 64-6198 or vehicle. Ten minutes later, they received ICV CRF, 200 ng/rat or vehicle; food was offered after 20 min. Results: Intraperitoneal (IP) pretreatment with Ro 64-6198 reversed the hypophagic effect induced by both restraint or CRF; the effect was statistically significant at the three doses tested (0.3, 1.0 or 2.5 mg/kg). ICV administration of the selective ORL1 receptor antagonist [Nphe1]NC(1–13)NH2 (two injections of 33 or 66 µg/rat) abolished the effect of Ro 64-6198 on CRF-induced anorexia. In freely feeding rats, Ro 64-6198 significantly increased feeding at 2.5, but not at 0.3 or 1.0 mg/kg; in food deprived rats, Ro 64-6198 (0.3 or 1.0 mg/kg) did not modify food intake. Thus, Reversal of Stress- and CRF-induced anorexia by Ro 64-6198 can be evoked at doses lower than those that are hyperphagic. Ro 64-6198 (1 or 2.5 mg/kg) did not modify the anorectic effect of E. coli lipopolysaccharide, suggesting that its effect is selective for Stress- or CRF-induced anorexia. Lastly, the benzodiazepine diazepam was unable to reduce the anorectic effect of CRF at the anxiolytic dose of 0.3 mg/kg, and partially reduced it at the hyperphagic dose of 1 mg/kg. Conclusions: The results of this study show that the non-peptidic ORL1 receptor agonist Ro 64-6198 markedly and selectively inhibits the anorectic effect of Stress and CRF, and provide evidence that this effect is mediated by ORL1 receptors. Thus, Ro 64-6198 may represent an interesting tool for treatment of Stress-induced anorexia.
Roberto Ciccocioppo - One of the best experts on this subject based on the ideXlab platform.
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Reversal of Stress- and CRF-induced anorexia in rats by the synthetic nociceptin/orphanin FQ receptor agonist, Ro 64-6198.
Psychopharmacology, 2002Co-Authors: Roberto Ciccocioppo, Michela Biondini, Lorena Antonelli, Juergen Wichmann, Francois Jenck, Maurizio MassiAbstract:Rationale: (1S,3aS)-8-(2,3,3,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198), a non-peptidic agonist for the opioid receptor-like1 (ORL1) receptor, exhibits anxiolytic properties in Stressful conditions. Objective: The present study was aimed at evaluating whether activation of ORL1 receptors by Ro 64-6198 may reverse the anorectic effect of restraint Stress or intracerebroventricular (ICV) CRF injection. Methods: In body restraint experiments, 20-h food deprived rats were treated with intraperitoneal (IP) injection of Ro 64-6198 or vehicle. Ten minutes later, they were confined in cylindrical Plexiglas tubes for 60 min and then returned to their cage with food. In CRF experiments, 20-h food deprived rats were IP injected with Ro 64-6198 or vehicle. Ten minutes later, they received ICV CRF, 200 ng/rat or vehicle; food was offered after 20 min. Results: Intraperitoneal (IP) pretreatment with Ro 64-6198 reversed the hypophagic effect induced by both restraint or CRF; the effect was statistically significant at the three doses tested (0.3, 1.0 or 2.5 mg/kg). ICV administration of the selective ORL1 receptor antagonist [Nphe1]NC(1–13)NH2 (two injections of 33 or 66 µg/rat) abolished the effect of Ro 64-6198 on CRF-induced anorexia. In freely feeding rats, Ro 64-6198 significantly increased feeding at 2.5, but not at 0.3 or 1.0 mg/kg; in food deprived rats, Ro 64-6198 (0.3 or 1.0 mg/kg) did not modify food intake. Thus, Reversal of Stress- and CRF-induced anorexia by Ro 64-6198 can be evoked at doses lower than those that are hyperphagic. Ro 64-6198 (1 or 2.5 mg/kg) did not modify the anorectic effect of E. coli lipopolysaccharide, suggesting that its effect is selective for Stress- or CRF-induced anorexia. Lastly, the benzodiazepine diazepam was unable to reduce the anorectic effect of CRF at the anxiolytic dose of 0.3 mg/kg, and partially reduced it at the hyperphagic dose of 1 mg/kg. Conclusions: The results of this study show that the non-peptidic ORL1 receptor agonist Ro 64-6198 markedly and selectively inhibits the anorectic effect of Stress and CRF, and provide evidence that this effect is mediated by ORL1 receptors. Thus, Ro 64-6198 may represent an interesting tool for treatment of Stress-induced anorexia.
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Reversal of Stress and crf induced anorexia in rats by the synthetic nociceptin orphanin fq receptor agonist ro 64 6198
Psychopharmacology, 2002Co-Authors: Roberto Ciccocioppo, Michela Biondini, Lorena Antonelli, Juergen Wichmann, Francois Jenck, Maurizio MassiAbstract:Rationale: (1S,3aS)-8-(2,3,3,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198), a non-peptidic agonist for the opioid receptor-like1 (ORL1) receptor, exhibits anxiolytic properties in Stressful conditions. Objective: The present study was aimed at evaluating whether activation of ORL1 receptors by Ro 64-6198 may reverse the anorectic effect of restraint Stress or intracerebroventricular (ICV) CRF injection. Methods: In body restraint experiments, 20-h food deprived rats were treated with intraperitoneal (IP) injection of Ro 64-6198 or vehicle. Ten minutes later, they were confined in cylindrical Plexiglas tubes for 60 min and then returned to their cage with food. In CRF experiments, 20-h food deprived rats were IP injected with Ro 64-6198 or vehicle. Ten minutes later, they received ICV CRF, 200 ng/rat or vehicle; food was offered after 20 min. Results: Intraperitoneal (IP) pretreatment with Ro 64-6198 reversed the hypophagic effect induced by both restraint or CRF; the effect was statistically significant at the three doses tested (0.3, 1.0 or 2.5 mg/kg). ICV administration of the selective ORL1 receptor antagonist [Nphe1]NC(1–13)NH2 (two injections of 33 or 66 µg/rat) abolished the effect of Ro 64-6198 on CRF-induced anorexia. In freely feeding rats, Ro 64-6198 significantly increased feeding at 2.5, but not at 0.3 or 1.0 mg/kg; in food deprived rats, Ro 64-6198 (0.3 or 1.0 mg/kg) did not modify food intake. Thus, Reversal of Stress- and CRF-induced anorexia by Ro 64-6198 can be evoked at doses lower than those that are hyperphagic. Ro 64-6198 (1 or 2.5 mg/kg) did not modify the anorectic effect of E. coli lipopolysaccharide, suggesting that its effect is selective for Stress- or CRF-induced anorexia. Lastly, the benzodiazepine diazepam was unable to reduce the anorectic effect of CRF at the anxiolytic dose of 0.3 mg/kg, and partially reduced it at the hyperphagic dose of 1 mg/kg. Conclusions: The results of this study show that the non-peptidic ORL1 receptor agonist Ro 64-6198 markedly and selectively inhibits the anorectic effect of Stress and CRF, and provide evidence that this effect is mediated by ORL1 receptors. Thus, Ro 64-6198 may represent an interesting tool for treatment of Stress-induced anorexia.
Paul Willner - One of the best experts on this subject based on the ideXlab platform.
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Treatment-resistant depression: are animal models of depression fit for purpose?
Psychopharmacology, 2015Co-Authors: Paul Willner, Catherine BelzungAbstract:Background Resistance to antidepressant drug treatment remains a major health problem. Animal models of depression are efficient in detecting effective treatments but have done little to increase the reach of antidepressant drugs. This may be because most animal models of depression target the Reversal of Stress-induced behavioural change, whereas treatment-resistant depression is typically associated with risk factors that predispose to the precipitation of depressive episodes by relatively low levels of Stress. Therefore, the search for treatments for resistant depression may require models that incorporate predisposing factors leading to heightened Stress responsiveness. Method Using a diathesis-Stress framework, we review developmental, genetic and genomic models against four criteria: (i) increased sensitivity to Stress precipitation of a depressive behavioural phenotype, (ii) resistance to chronic treatment with conventional antidepressants, (iii) a good response to novel modes of antidepressant treatment (e.g. ketamine; deep brain stimulation) that are reported to be effective in treatment-resistant depression and (iv) a parallel to a known clinical risk factor. Results We identify 18 models that may have some potential. All require further validation. Currently, the most promising are the Wistar-Kyoto (WKY) and congenital learned helplessness (cLH) rat strains, the high anxiety behaviour (HAB) mouse strain and the CB1 receptor knockout and OCT2 null mutant mouse strains. Conclusion Further development is needed to validate models of antidepressant resistance that are fit for purpose. The criteria used in this review may provide a helpful framework to guide research in this area.
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Treatment-resistant depression: are animal models of depression fit for purpose?
Psychopharmacology, 2015Co-Authors: Paul Willner, Catherine BelzungAbstract:Resistance to antidepressant drug treatment remains a major health problem. Animal models of depression are efficient in detecting effective treatments but have done little to increase the reach of antidepressant drugs. This may be because most animal models of depression target the Reversal of Stress-induced behavioural change, whereas treatment-resistant depression is typically associated with risk factors that predispose to the precipitation of depressive episodes by relatively low levels of Stress. Therefore, the search for treatments for resistant depression may require models that incorporate predisposing factors leading to heightened Stress responsiveness. Using a diathesis-Stress framework, we review developmental, genetic and genomic models against four criteria: (i) increased sensitivity to Stress precipitation of a depressive behavioural phenotype, (ii) resistance to chronic treatment with conventional antidepressants, (iii) a good response to novel modes of antidepressant treatment (e.g. ketamine; deep brain stimulation) that are reported to be effective in treatment-resistant depression and (iv) a parallel to a known clinical risk factor. We identify 18 models that may have some potential. All require further validation. Currently, the most promising are the Wistar-Kyoto (WKY) and congenital learned helplessness (cLH) rat strains, the high anxiety behaviour (HAB) mouse strain and the CB1 receptor knockout and OCT2 null mutant mouse strains. Further development is needed to validate models of antidepressant resistance that are fit for purpose. The criteria used in this review may provide a helpful framework to guide research in this area.
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stereospecific Reversal of Stress induced anhedonia by mianserin and its enantiomer
Psychopharmacology, 1994Co-Authors: Survjit Cheeta, Chris L.e. Broekkamp, Paul WillnerAbstract:Chronic sequential exposure to a variety of mild unpredictable Stressors has previously been found to depress the consumption of a dilute (1%) sucrose solution and to inhibit food-induced place preference conditioning. In the present study, using a simplified version of the mild Stress procedure, the decreased sucrose intake was reversed by chronic (4 weeks) treatment with the atypical antidepressant mianserin. The racemic compound (±)-mianserin (5 mg/kg per day) and one of its enantiomers, (+)-mianserin (2.5 mg/kg) were effective in this model; a lower dose of (±)-mianserin (2.5 mg/kg), and the other enantiomer, (−)-mianserin (2.5 mg/kg), were ineffective. Vehicle-treated Stressed animals were also subsensitive to food reward in the place conditioning procedure: normal place preference conditioning was reinstated by chronic treatment with (±)-mianserin (5 mg/kg) or (+)-mianserin, but not by the lower dose of (±)-mianserin (2.5 mg/kg) or by (−)-mianserin. Raclopride (100 µg/kg) reinstated the decrease in sucrose intake in Stressed animals successfully treated with (±)- or (+)-mianserin. The results suggest that (+)-mianserin is the active enantiomer in reversing chronic mild Stress-induced anhedonia, and further support the hypothesis of a dopaminergic mechanism of antidepressant action in this paradigm.
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Reversal of Stress-induced anhedonia by the dopamine receptor agonist, pramipexole
Psychopharmacology, 1994Co-Authors: Paul Willner, Survjit Cheeta, Spiros Lappas, Richard MuscatAbstract:Chronic exposure to mild unpredictable Stress has previously been found to depress the consumption of a palatable (1%) sucrose solution, and to attenuate food-induced place preference conditioning. In this study the effects of pramipexole (SND-919), a dopamine D_2 agonist, were studied during 7–9 weeks of chronic treatment. Pramipexole (1.0 mg/kg per day) reversed the suppression of sucrose intake in Stressed animals, increasing sucrose intakes above the levels seen in untreated nonStressed controls. Pramipexole also increased sucrose intake in nonStressed animals; these effects were accompanied by increases in water intake and tended to correlate with weight loss. Drug-treated Stressed animals also lost weight, but in this case water intake was unaffected. A second group of animals received a higher dose of pramipexole (2.0 mg/kg per day). The effects of the two doses were very similar. After three weeks of treatment, these animals were switched to a lower dose of pramipexole (0.1 mg/kg per day). Increases in sucrose intake were maintained over three weeks of treatment at the lower dose, with significant recovery of body weight. Two further groups received the same doses of pramipexole (1.0 mg/kg for 6 weeks or 2.0 mg/kg for 3 weeks followed by 0.1 mg/kg thereafter), but received intermittent (twice-weekly) drug treatment. Intermittent pramipexole treatments also tended to increase sucrose intakes, but the results were less consistent from week to week. Following 6–8 weeks of pramipexole treatment, food-induced place preference conditioning was studied in all animals. Untreated Stressed animals showed no evidence of place conditioning. Normal conditioning was seen in both groups of Stressed animals treated daily with pramipexole (at 1.0 and 0.1 mg/kg) and in the group treated twice weekly at the higher dose (1.0 mg/kg); intermittent treatment at the lower dose (0.1 mg/kg) was ineffective. The results indicate that pramipexole exerts rapid anti-anhedonic effects in the chronic mild Stress model. This conclusion is complicated, but not undermined, by drug-induced weight loss and by the presence of significant drug effects in nonStressed control animals.
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Stereospecific Reversal of Stress-induced anhedonia by mianserin and its (+)-enantiomer.
Psychopharmacology, 1994Co-Authors: Survjit Cheeta, Chris L.e. Broekkamp, Paul WillnerAbstract:Chronic sequential exposure to a variety of mild unpredictable Stressors has previously been found to depress the consumption of a dilute (1%) sucrose solution and to inhibit food-induced place preference conditioning. In the present study, using a simplified version of the mild Stress procedure, the decreased sucrose intake was reversed by chronic (4 weeks) treatment with the atypical antidepressant mianserin. The racemic compound (±)-mianserin (5 mg/kg per day) and one of its enantiomers, (+)-mianserin (2.5 mg/kg) were effective in this model; a lower dose of (±)-mianserin (2.5 mg/kg), and the other enantiomer, (−)-mianserin (2.5 mg/kg), were ineffective. Vehicle-treated Stressed animals were also subsensitive to food reward in the place conditioning procedure: normal place preference conditioning was reinstated by chronic treatment with (±)-mianserin (5 mg/kg) or (+)-mianserin, but not by the lower dose of (±)-mianserin (2.5 mg/kg) or by (−)-mianserin. Raclopride (100 µg/kg) reinstated the decrease in sucrose intake in Stressed animals successfully treated with (±)- or (+)-mianserin. The results suggest that (+)-mianserin is the active enantiomer in reversing chronic mild Stress-induced anhedonia, and further support the hypothesis of a dopaminergic mechanism of antidepressant action in this paradigm.
Michela Biondini - One of the best experts on this subject based on the ideXlab platform.
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Reversal of Stress- and CRF-induced anorexia in rats by the synthetic nociceptin/orphanin FQ receptor agonist, Ro 64-6198.
Psychopharmacology, 2002Co-Authors: Roberto Ciccocioppo, Michela Biondini, Lorena Antonelli, Juergen Wichmann, Francois Jenck, Maurizio MassiAbstract:Rationale: (1S,3aS)-8-(2,3,3,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198), a non-peptidic agonist for the opioid receptor-like1 (ORL1) receptor, exhibits anxiolytic properties in Stressful conditions. Objective: The present study was aimed at evaluating whether activation of ORL1 receptors by Ro 64-6198 may reverse the anorectic effect of restraint Stress or intracerebroventricular (ICV) CRF injection. Methods: In body restraint experiments, 20-h food deprived rats were treated with intraperitoneal (IP) injection of Ro 64-6198 or vehicle. Ten minutes later, they were confined in cylindrical Plexiglas tubes for 60 min and then returned to their cage with food. In CRF experiments, 20-h food deprived rats were IP injected with Ro 64-6198 or vehicle. Ten minutes later, they received ICV CRF, 200 ng/rat or vehicle; food was offered after 20 min. Results: Intraperitoneal (IP) pretreatment with Ro 64-6198 reversed the hypophagic effect induced by both restraint or CRF; the effect was statistically significant at the three doses tested (0.3, 1.0 or 2.5 mg/kg). ICV administration of the selective ORL1 receptor antagonist [Nphe1]NC(1–13)NH2 (two injections of 33 or 66 µg/rat) abolished the effect of Ro 64-6198 on CRF-induced anorexia. In freely feeding rats, Ro 64-6198 significantly increased feeding at 2.5, but not at 0.3 or 1.0 mg/kg; in food deprived rats, Ro 64-6198 (0.3 or 1.0 mg/kg) did not modify food intake. Thus, Reversal of Stress- and CRF-induced anorexia by Ro 64-6198 can be evoked at doses lower than those that are hyperphagic. Ro 64-6198 (1 or 2.5 mg/kg) did not modify the anorectic effect of E. coli lipopolysaccharide, suggesting that its effect is selective for Stress- or CRF-induced anorexia. Lastly, the benzodiazepine diazepam was unable to reduce the anorectic effect of CRF at the anxiolytic dose of 0.3 mg/kg, and partially reduced it at the hyperphagic dose of 1 mg/kg. Conclusions: The results of this study show that the non-peptidic ORL1 receptor agonist Ro 64-6198 markedly and selectively inhibits the anorectic effect of Stress and CRF, and provide evidence that this effect is mediated by ORL1 receptors. Thus, Ro 64-6198 may represent an interesting tool for treatment of Stress-induced anorexia.
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Reversal of Stress and crf induced anorexia in rats by the synthetic nociceptin orphanin fq receptor agonist ro 64 6198
Psychopharmacology, 2002Co-Authors: Roberto Ciccocioppo, Michela Biondini, Lorena Antonelli, Juergen Wichmann, Francois Jenck, Maurizio MassiAbstract:Rationale: (1S,3aS)-8-(2,3,3,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198), a non-peptidic agonist for the opioid receptor-like1 (ORL1) receptor, exhibits anxiolytic properties in Stressful conditions. Objective: The present study was aimed at evaluating whether activation of ORL1 receptors by Ro 64-6198 may reverse the anorectic effect of restraint Stress or intracerebroventricular (ICV) CRF injection. Methods: In body restraint experiments, 20-h food deprived rats were treated with intraperitoneal (IP) injection of Ro 64-6198 or vehicle. Ten minutes later, they were confined in cylindrical Plexiglas tubes for 60 min and then returned to their cage with food. In CRF experiments, 20-h food deprived rats were IP injected with Ro 64-6198 or vehicle. Ten minutes later, they received ICV CRF, 200 ng/rat or vehicle; food was offered after 20 min. Results: Intraperitoneal (IP) pretreatment with Ro 64-6198 reversed the hypophagic effect induced by both restraint or CRF; the effect was statistically significant at the three doses tested (0.3, 1.0 or 2.5 mg/kg). ICV administration of the selective ORL1 receptor antagonist [Nphe1]NC(1–13)NH2 (two injections of 33 or 66 µg/rat) abolished the effect of Ro 64-6198 on CRF-induced anorexia. In freely feeding rats, Ro 64-6198 significantly increased feeding at 2.5, but not at 0.3 or 1.0 mg/kg; in food deprived rats, Ro 64-6198 (0.3 or 1.0 mg/kg) did not modify food intake. Thus, Reversal of Stress- and CRF-induced anorexia by Ro 64-6198 can be evoked at doses lower than those that are hyperphagic. Ro 64-6198 (1 or 2.5 mg/kg) did not modify the anorectic effect of E. coli lipopolysaccharide, suggesting that its effect is selective for Stress- or CRF-induced anorexia. Lastly, the benzodiazepine diazepam was unable to reduce the anorectic effect of CRF at the anxiolytic dose of 0.3 mg/kg, and partially reduced it at the hyperphagic dose of 1 mg/kg. Conclusions: The results of this study show that the non-peptidic ORL1 receptor agonist Ro 64-6198 markedly and selectively inhibits the anorectic effect of Stress and CRF, and provide evidence that this effect is mediated by ORL1 receptors. Thus, Ro 64-6198 may represent an interesting tool for treatment of Stress-induced anorexia.
Lorena Antonelli - One of the best experts on this subject based on the ideXlab platform.
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Reversal of Stress- and CRF-induced anorexia in rats by the synthetic nociceptin/orphanin FQ receptor agonist, Ro 64-6198.
Psychopharmacology, 2002Co-Authors: Roberto Ciccocioppo, Michela Biondini, Lorena Antonelli, Juergen Wichmann, Francois Jenck, Maurizio MassiAbstract:Rationale: (1S,3aS)-8-(2,3,3,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198), a non-peptidic agonist for the opioid receptor-like1 (ORL1) receptor, exhibits anxiolytic properties in Stressful conditions. Objective: The present study was aimed at evaluating whether activation of ORL1 receptors by Ro 64-6198 may reverse the anorectic effect of restraint Stress or intracerebroventricular (ICV) CRF injection. Methods: In body restraint experiments, 20-h food deprived rats were treated with intraperitoneal (IP) injection of Ro 64-6198 or vehicle. Ten minutes later, they were confined in cylindrical Plexiglas tubes for 60 min and then returned to their cage with food. In CRF experiments, 20-h food deprived rats were IP injected with Ro 64-6198 or vehicle. Ten minutes later, they received ICV CRF, 200 ng/rat or vehicle; food was offered after 20 min. Results: Intraperitoneal (IP) pretreatment with Ro 64-6198 reversed the hypophagic effect induced by both restraint or CRF; the effect was statistically significant at the three doses tested (0.3, 1.0 or 2.5 mg/kg). ICV administration of the selective ORL1 receptor antagonist [Nphe1]NC(1–13)NH2 (two injections of 33 or 66 µg/rat) abolished the effect of Ro 64-6198 on CRF-induced anorexia. In freely feeding rats, Ro 64-6198 significantly increased feeding at 2.5, but not at 0.3 or 1.0 mg/kg; in food deprived rats, Ro 64-6198 (0.3 or 1.0 mg/kg) did not modify food intake. Thus, Reversal of Stress- and CRF-induced anorexia by Ro 64-6198 can be evoked at doses lower than those that are hyperphagic. Ro 64-6198 (1 or 2.5 mg/kg) did not modify the anorectic effect of E. coli lipopolysaccharide, suggesting that its effect is selective for Stress- or CRF-induced anorexia. Lastly, the benzodiazepine diazepam was unable to reduce the anorectic effect of CRF at the anxiolytic dose of 0.3 mg/kg, and partially reduced it at the hyperphagic dose of 1 mg/kg. Conclusions: The results of this study show that the non-peptidic ORL1 receptor agonist Ro 64-6198 markedly and selectively inhibits the anorectic effect of Stress and CRF, and provide evidence that this effect is mediated by ORL1 receptors. Thus, Ro 64-6198 may represent an interesting tool for treatment of Stress-induced anorexia.
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Reversal of Stress and crf induced anorexia in rats by the synthetic nociceptin orphanin fq receptor agonist ro 64 6198
Psychopharmacology, 2002Co-Authors: Roberto Ciccocioppo, Michela Biondini, Lorena Antonelli, Juergen Wichmann, Francois Jenck, Maurizio MassiAbstract:Rationale: (1S,3aS)-8-(2,3,3,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (Ro 64-6198), a non-peptidic agonist for the opioid receptor-like1 (ORL1) receptor, exhibits anxiolytic properties in Stressful conditions. Objective: The present study was aimed at evaluating whether activation of ORL1 receptors by Ro 64-6198 may reverse the anorectic effect of restraint Stress or intracerebroventricular (ICV) CRF injection. Methods: In body restraint experiments, 20-h food deprived rats were treated with intraperitoneal (IP) injection of Ro 64-6198 or vehicle. Ten minutes later, they were confined in cylindrical Plexiglas tubes for 60 min and then returned to their cage with food. In CRF experiments, 20-h food deprived rats were IP injected with Ro 64-6198 or vehicle. Ten minutes later, they received ICV CRF, 200 ng/rat or vehicle; food was offered after 20 min. Results: Intraperitoneal (IP) pretreatment with Ro 64-6198 reversed the hypophagic effect induced by both restraint or CRF; the effect was statistically significant at the three doses tested (0.3, 1.0 or 2.5 mg/kg). ICV administration of the selective ORL1 receptor antagonist [Nphe1]NC(1–13)NH2 (two injections of 33 or 66 µg/rat) abolished the effect of Ro 64-6198 on CRF-induced anorexia. In freely feeding rats, Ro 64-6198 significantly increased feeding at 2.5, but not at 0.3 or 1.0 mg/kg; in food deprived rats, Ro 64-6198 (0.3 or 1.0 mg/kg) did not modify food intake. Thus, Reversal of Stress- and CRF-induced anorexia by Ro 64-6198 can be evoked at doses lower than those that are hyperphagic. Ro 64-6198 (1 or 2.5 mg/kg) did not modify the anorectic effect of E. coli lipopolysaccharide, suggesting that its effect is selective for Stress- or CRF-induced anorexia. Lastly, the benzodiazepine diazepam was unable to reduce the anorectic effect of CRF at the anxiolytic dose of 0.3 mg/kg, and partially reduced it at the hyperphagic dose of 1 mg/kg. Conclusions: The results of this study show that the non-peptidic ORL1 receptor agonist Ro 64-6198 markedly and selectively inhibits the anorectic effect of Stress and CRF, and provide evidence that this effect is mediated by ORL1 receptors. Thus, Ro 64-6198 may represent an interesting tool for treatment of Stress-induced anorexia.