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Autoradiographic distribution of [3H]-befloxatone, a selective and reversible MAO-A inhibitor in the rat brain
2365
Poster session IV
BIOL. PSYCHIATRY 1997;42:15-297S
190-51 chronic Cltalopram and release of brain 5·HT In experimental hepatic encephalopathy P.B.F. Bergqvist, C. Wikell, S. Hjorth 1 , G. Apelqvist, F. Bengtsson. Department of Clinical Pharmacology. Lund University, Lund. Sweden. 1 Department of PharmaC()logy. University of Gothenburg. Gothenburg, Sweden Hepatic encephalopathy (HE) can be observed in patients with chronic liver failure. HE enC()mpasses a neuropsychiatric syndrome including both affective and psychotic symptoms. Chronic experimental HE (portacaval shunt in rats; PCS), represents a steady-state CNS pathology without signs of neuronal destruction but with clear behavioral abnormalities present. The experimental HE situation reflects a primary neura-transmission failure in the brain and thus may also have distinct bearings on some major entities relevant in both affective and psychotic disorders, especially in patients with impaired liver function. In the present study, effects 01 the 5-HT reuptake inhibitor citalopram (CIT) on brain 5-HT release in experimental PSE were investigated. Neocortical administration of CIT (1.0 ,..M) did not affect the brain 5-HT output In PCS compared with sham-operated rats evidencing that a previous described uncoupling between increased 5-HT tumover and release in PCS rats is not accounted for by an accelerated brain 5-HT reuptake in this condition. Systemic administration of CIT (5 mglkg) resulted In a more pronounced attenuation of the brain 5-HT release In PCS than sham rats possibly indicating a higher susceptibility to reuptake Inhibition in HE. A KCI (60 mM) challenge in the presence of locally administered CIT induced a more marked neocortical 5-HT response In PCS than sham rats confirming previous results of a higher than normal amount of 5-HT available for depolarization-Induced release In PCS rats. Although the pharmacodynamics for CIT were investigated, also the likelihood of a parallel pharmacoklnetic alteration existing for this drug in the PCS condition was evidenced. A restricted use for 5-HT-acting drugs In patients with liver Insufficiency is therefore strongly advocated until the pharmacodynamics and -kinetics coming into play in these not clinically uncommon situations have been further delineated.
190-61 Early Isolation Increases the antlimmobility effect of paroxetlne In the mice forced swImming test N. Wongwitdecha, C. Kasemsook. Department of Pharmacology. FaCUlty of Science. Mahidol University, Rama VI Road. Bangkok 10400. Thailand The aims of the present experiments were to Investigate the effects of isolation rearing on the mice forced swimming behavior, and compare the effects of a selective serotonin reuptake inhibitor, paroxetine on this behavior In Isolation and socially reared mice. Methods: Male mice were raised at 21 days of age, and housed either alone (isolation rearing) or in groups of five mice/cage (social rearing) for four weeks. After a pre-exposure to the forced swimming for 15 min the day before, each mouse was allowed to swim in a glass cylinder (height 24 cm, diameter 12 cm) containing 8 cm of water maintained at 25 :: 1 • C for a 5 min test. Their behaviors were quantified by measuring the time they spent floating almost motionless (immobility time) or struggling (Porsoll et al., 1978, Eur J PharmaC()147, 379-391). Results: The results demonstrate that the forced swimming behavior of drug free mice reared In Isolation was not significantly difference from SOCially reared mice. Pretreatment of paroxetine (5, 10, 15 mglkg I.p., 24 h and 1 h before a 5 min test) in both Isolation and socially reared mice produced a dose-related reduction In immobility time and elevation in struggling compared to the vehicle group. These effects were greater in the Isolation reared than the socially reared mice. Conclusion: These results indicate that isolation rearing Increases the sensitivity to the antidepressant-like effect of the selective serotonin reuptake Inhibitor, paroxetine.
190-71 Chronic treatment with amitriptyline decreases CRF·R1 receptor mRNA levels In the rat amygdala J.M. Aubry, G. PozzolI, W.W. Vale. Clayton Found. Labs. for Peptide Biology. The Salk Institute. La Jolla CA, USA Patients with major depression exhibit signs of corticotropin-releasing fac• tor (CRF) hypersecretion, such as Increased hypothalamo-pitultary-adrenal (HPA) axis activity. Hyperactivity of the HPA axis Is no longer present In de• pressed patients who have been successfully treated with antidepressants and a decrease in hypothalamic CRF mRNA has been reported In animal
models of depression treated chronically with antidepressants. However, the Impact of antidepressant drugs on the regulation of CRF receptors remain to be elucidated. The aim of this study was to Investigate whether acute (10 days) and chronic (4 weeks) treatment with amitriptyline, a clinically efficient tricyclic antidepressant, has an effect on CRF, CRF-Rl and CRF-R2 gene expres• sion in the rat hypothalamus and amygdala. In situ hybridization (ISH) with riboprobes specific for CRF, CRF-Rl and CRF-R2 were used lor the study. Semi-quantitative analysis of ISH signals over the hypothalamic paraven• tricular nucleus (PVN), and selected nucleus 01 the amygdala showed that only chronic treatment with amitriptyline produced a significant decrease in CRF mRNA in the PVN (to 33% of controls). CRF-Rl mRNA level was not different after acute treatment either In the PVN or In the amygdala. On the contrary, after chronic treatment, there was a significant decrease of CRF-Rl mRNA levels in the baso-Iateral (to 60% of cont.) and in the medial amygdala (to 70% of cont.). There was no significant changes for CRF-R2 mRNA either after acute or chronic treatment. These results suggest that tricyclic antidepressants may exert part of their effects through modulation of CRF·Rl gene expression in the amygdala.
190-81 S-adenosylmethlonlne Effects of an antidepressant treatment on plasma levels A. Lucca, R. Conca, E. Smeraldl. IRCCS H. San Raffaele, Department of Neuropsychiatry Science. University of Milan, via Prlnett/29, 20127 Milan. Italy Our purposes in this preliminary investigation were: a) an exploratory study of endogenous S·adenosylmethlonlne (SAMe) plasma levels In depreSsed patients; b) to examine whether SAMe plasma levels change after antide• pressant treatment with f1uvoxamlne, a selective serotonin uptake Inhibitor (SSRI) Methods: Forty inpatients meeting DSM-IV criteria for Major Depression were treated for 28 days with f1uvoxamine 300 mg per day. An Investigator administered the 21-items Hamilton Depression to each patient at baseline and weekly thereafter. Blood samples for the analysis of plasma SAMe levels were collected after the wash out and at each week of the study and immediately stored at -20·C until analysis. Twenty Individuals were selected as control group. Results: No significant differences between controls and patients was found in basal plasma SAMe levels, even if for the depressed group the levels fluctuate over a wider range. Concentrations of SAMe Increased significantly over time In all patients independently from the clinical response. We think that these findings need to be investigated In a larger group of SUbjects and also in patients with different state of Illness (mania).
190-91 selective Autoradlographlc distribution of [3H]-befloxatone, a and reversible MAO·A Inhibitor In the rat brain C. Sauvage, O. Curet. G. Damolseau, J. Benavides, B. Scatton. CNS Research Department, Synthe/abo Recherche, Ruell-Malmaison, France Belloxatone is an oxazolidinone derivative belonging to the new generation of reversible and selective MAo-A Inhibitors. The present study was undertaken to characterize the autoradiographic distribution In vitro, fHj-befioxatone binding to rat brain sections was saturable, reversible and of high affinity (Kd 1.3 nM). The non-specific binding, determined In the presence of 10 ItM harmaline, represented less than 5% of total binding at a concentration of 2 nM fH]-befioxatone. Displacing potency of substrates and MAo-A inhibitors correlated highly and positively with their corresponding values from MAQ-A Inhibition assays and demonstrated that fHl-befioxatone binding sites pos• sess the pharmacological properties of MAO-A. [3Hl-befloxatone binding was highest In the locus coeruleus and interpeduncular nucleus. High levels of binding were also found In the dorsal raph~. habenula and In the nucleus of the solitary tract. The density of fH]·befioxatone binding sites In ral brain regions correlated well with that reported for MAO-A. [3Hj-befloxatone binding was displaced In a dose-dependent manner by increasing doses of b?floxat~ne wi~ an 1050 of mglkg. po In the frontal cortex. Following in VIVO administration (30 ,..CVrat,l.v.), (-lHl-befloxatone binding in brain showed an heterogenous distribution which closely correlated with that observed In vitro. In conclusion, [3Hl-befloxatone appears to be a suitable radioligand tor the In vitro and in vivo labelling of MAO-A. Befloxatone might be a ligand 01 choice for PET-scan Imaging of this enzyme In the brain.
=
O.O?
Poster session IV
BIOL. PSYCHIATRY 1997;42:15-297S
190-51 chronic Cltalopram and release of brain 5·HT In experimental hepatic encephalopathy P.B.F. Bergqvist, C. Wikell, S. Hjorth 1 , G. Apelqvist, F. Bengtsson. Department of Clinical Pharmacology. Lund University, Lund. Sweden. 1 Department of PharmaC()logy. University of Gothenburg. Gothenburg, Sweden Hepatic encephalopathy (HE) can be observed in patients with chronic liver failure. HE enC()mpasses a neuropsychiatric syndrome including both affective and psychotic symptoms. Chronic experimental HE (portacaval shunt in rats; PCS), represents a steady-state CNS pathology without signs of neuronal destruction but with clear behavioral abnormalities present. The experimental HE situation reflects a primary neura-transmission failure in the brain and thus may also have distinct bearings on some major entities relevant in both affective and psychotic disorders, especially in patients with impaired liver function. In the present study, effects 01 the 5-HT reuptake inhibitor citalopram (CIT) on brain 5-HT release in experimental PSE were investigated. Neocortical administration of CIT (1.0 ,..M) did not affect the brain 5-HT output In PCS compared with sham-operated rats evidencing that a previous described uncoupling between increased 5-HT tumover and release in PCS rats is not accounted for by an accelerated brain 5-HT reuptake in this condition. Systemic administration of CIT (5 mglkg) resulted In a more pronounced attenuation of the brain 5-HT release In PCS than sham rats possibly indicating a higher susceptibility to reuptake Inhibition in HE. A KCI (60 mM) challenge in the presence of locally administered CIT induced a more marked neocortical 5-HT response In PCS than sham rats confirming previous results of a higher than normal amount of 5-HT available for depolarization-Induced release In PCS rats. Although the pharmacodynamics for CIT were investigated, also the likelihood of a parallel pharmacoklnetic alteration existing for this drug in the PCS condition was evidenced. A restricted use for 5-HT-acting drugs In patients with liver Insufficiency is therefore strongly advocated until the pharmacodynamics and -kinetics coming into play in these not clinically uncommon situations have been further delineated.
190-61 Early Isolation Increases the antlimmobility effect of paroxetlne In the mice forced swImming test N. Wongwitdecha, C. Kasemsook. Department of Pharmacology. FaCUlty of Science. Mahidol University, Rama VI Road. Bangkok 10400. Thailand The aims of the present experiments were to Investigate the effects of isolation rearing on the mice forced swimming behavior, and compare the effects of a selective serotonin reuptake inhibitor, paroxetine on this behavior In Isolation and socially reared mice. Methods: Male mice were raised at 21 days of age, and housed either alone (isolation rearing) or in groups of five mice/cage (social rearing) for four weeks. After a pre-exposure to the forced swimming for 15 min the day before, each mouse was allowed to swim in a glass cylinder (height 24 cm, diameter 12 cm) containing 8 cm of water maintained at 25 :: 1 • C for a 5 min test. Their behaviors were quantified by measuring the time they spent floating almost motionless (immobility time) or struggling (Porsoll et al., 1978, Eur J PharmaC()147, 379-391). Results: The results demonstrate that the forced swimming behavior of drug free mice reared In Isolation was not significantly difference from SOCially reared mice. Pretreatment of paroxetine (5, 10, 15 mglkg I.p., 24 h and 1 h before a 5 min test) in both Isolation and socially reared mice produced a dose-related reduction In immobility time and elevation in struggling compared to the vehicle group. These effects were greater in the Isolation reared than the socially reared mice. Conclusion: These results indicate that isolation rearing Increases the sensitivity to the antidepressant-like effect of the selective serotonin reuptake Inhibitor, paroxetine.
190-71 Chronic treatment with amitriptyline decreases CRF·R1 receptor mRNA levels In the rat amygdala J.M. Aubry, G. PozzolI, W.W. Vale. Clayton Found. Labs. for Peptide Biology. The Salk Institute. La Jolla CA, USA Patients with major depression exhibit signs of corticotropin-releasing fac• tor (CRF) hypersecretion, such as Increased hypothalamo-pitultary-adrenal (HPA) axis activity. Hyperactivity of the HPA axis Is no longer present In de• pressed patients who have been successfully treated with antidepressants and a decrease in hypothalamic CRF mRNA has been reported In animal
models of depression treated chronically with antidepressants. However, the Impact of antidepressant drugs on the regulation of CRF receptors remain to be elucidated. The aim of this study was to Investigate whether acute (10 days) and chronic (4 weeks) treatment with amitriptyline, a clinically efficient tricyclic antidepressant, has an effect on CRF, CRF-Rl and CRF-R2 gene expres• sion in the rat hypothalamus and amygdala. In situ hybridization (ISH) with riboprobes specific for CRF, CRF-Rl and CRF-R2 were used lor the study. Semi-quantitative analysis of ISH signals over the hypothalamic paraven• tricular nucleus (PVN), and selected nucleus 01 the amygdala showed that only chronic treatment with amitriptyline produced a significant decrease in CRF mRNA in the PVN (to 33% of controls). CRF-Rl mRNA level was not different after acute treatment either In the PVN or In the amygdala. On the contrary, after chronic treatment, there was a significant decrease of CRF-Rl mRNA levels in the baso-Iateral (to 60% of cont.) and in the medial amygdala (to 70% of cont.). There was no significant changes for CRF-R2 mRNA either after acute or chronic treatment. These results suggest that tricyclic antidepressants may exert part of their effects through modulation of CRF·Rl gene expression in the amygdala.
190-81 S-adenosylmethlonlne Effects of an antidepressant treatment on plasma levels A. Lucca, R. Conca, E. Smeraldl. IRCCS H. San Raffaele, Department of Neuropsychiatry Science. University of Milan, via Prlnett/29, 20127 Milan. Italy Our purposes in this preliminary investigation were: a) an exploratory study of endogenous S·adenosylmethlonlne (SAMe) plasma levels In depreSsed patients; b) to examine whether SAMe plasma levels change after antide• pressant treatment with f1uvoxamlne, a selective serotonin uptake Inhibitor (SSRI) Methods: Forty inpatients meeting DSM-IV criteria for Major Depression were treated for 28 days with f1uvoxamine 300 mg per day. An Investigator administered the 21-items Hamilton Depression to each patient at baseline and weekly thereafter. Blood samples for the analysis of plasma SAMe levels were collected after the wash out and at each week of the study and immediately stored at -20·C until analysis. Twenty Individuals were selected as control group. Results: No significant differences between controls and patients was found in basal plasma SAMe levels, even if for the depressed group the levels fluctuate over a wider range. Concentrations of SAMe Increased significantly over time In all patients independently from the clinical response. We think that these findings need to be investigated In a larger group of SUbjects and also in patients with different state of Illness (mania).
190-91 selective Autoradlographlc distribution of [3H]-befloxatone, a and reversible MAO·A Inhibitor In the rat brain C. Sauvage, O. Curet. G. Damolseau, J. Benavides, B. Scatton. CNS Research Department, Synthe/abo Recherche, Ruell-Malmaison, France Belloxatone is an oxazolidinone derivative belonging to the new generation of reversible and selective MAo-A Inhibitors. The present study was undertaken to characterize the autoradiographic distribution In vitro, fHj-befioxatone binding to rat brain sections was saturable, reversible and of high affinity (Kd 1.3 nM). The non-specific binding, determined In the presence of 10 ItM harmaline, represented less than 5% of total binding at a concentration of 2 nM fH]-befioxatone. Displacing potency of substrates and MAo-A inhibitors correlated highly and positively with their corresponding values from MAQ-A Inhibition assays and demonstrated that fHl-befioxatone binding sites pos• sess the pharmacological properties of MAO-A. [3Hl-befloxatone binding was highest In the locus coeruleus and interpeduncular nucleus. High levels of binding were also found In the dorsal raph~. habenula and In the nucleus of the solitary tract. The density of fH]·befioxatone binding sites In ral brain regions correlated well with that reported for MAO-A. [3Hj-befloxatone binding was displaced In a dose-dependent manner by increasing doses of b?floxat~ne wi~ an 1050 of mglkg. po In the frontal cortex. Following in VIVO administration (30 ,..CVrat,l.v.), (-lHl-befloxatone binding in brain showed an heterogenous distribution which closely correlated with that observed In vitro. In conclusion, [3Hl-befloxatone appears to be a suitable radioligand tor the In vitro and in vivo labelling of MAO-A. Befloxatone might be a ligand 01 choice for PET-scan Imaging of this enzyme In the brain.
=
O.O?