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P.2.d.017 Pharmacological profile of Lu AA21004, a novel multi-target drug for the treatment of mood disorders
P.2.d Affective disorders and antidepressants - Antidepressants (basic) ratio proteins was evaluated by Western Blot analysis. Wistar rats received acutely or chronically (once a day for 7 days), intraperitoneally (Lp.) injection ofamibegron (1,5 and IOmg/kg), tricyclic antidepressant (TCA) clomipramine (50mg/kg), selective serotonin reuptake inhibitor (SSRI) citalopram (15 mg/kg) or vehicles, respectively. The influence of stress-related conditions was studied in rats subjected to the acute (4 h) or repeated (4 h/day for 7 days) restraint stress, made prior to the FST procedure. Both acute and repeated administration of amibegron (5 and 10 mg/kg) decrased the immobility time both under basal conditions and after stress exposure. In non stressed animals, amibegron (IOmg/kg) increased hippocampal expression of BDNF and CREB proteins (p < 0.05) as well as of BDNF and Bcl-2/Bax ratio (p < 0.05; P < 0.01) after acute or repeated treatment, respectively. Both acute and repeated restraint stress procedure increased the immobility time in FST, considered as index of "depressive like behavior", in vehicle and SR58611A (1 mg/kg/day) injected stressed animals in comparison to control NST group (p < 0.05). Furthermore, rats showed lower hippocampal BDNF and Bcl-2/Bax ratio proteins expression in control stressed animals compared to control NST group (p<0.05; p
1P.2.d.0171 Pharmacological profile of Lu AA21004, a novel multi-target drug for the treatment of mood disorders A Mmk1 ., L.T. Brennum2 , S. Fallon3 , S. Bisulc03 , K. Frederiksen2 , B. Bang-Andersen2 , AB. Lassen2 , H. Zhong3 , C. Sanchez3 , T.B. Stensb012 . 1 H. Lundbeck A/S, Department of Neurophysi%gy, Copenhagen-Va/by, Denmark; 2 H. Lundbeck A/S, Research, Va/by-Copenhagen, Denmark; 3Lundbeck Research USA, Research, New Jersey, USA
Purpose of the study: Significant unmet needs in the treatment of depression and anxiety remain, despite the existence of several current treatment options. Lu AA21004 is a novel compound with a unique pharmacological profile. Lu AA21004 is a potent 5-HT3 receptor antagonist (h5-HT3A receptors: Kj =4.5 nM), 5-HTIA receptor agonist (h5-HTIA receptors: Kj = 15 nM) and 5-HT transporter inhibitor (h5-HTT ICso = 5.4 nM). The aim of the present research was to study the effects of Lu AA21004 on neurotransmitter levels in the brain and to test the compound in preclinical models predictive of anxiolytic- and antidepressant-like effects.
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Methods: The acute effects ofLu AA21004 (2.5-lOmg/kg, sc) on extracellular neurotransmitter [serotonin (5-HT), noradrenaline (NA), dopamine (DA), acetylcholine (ACh)] levels were measured by microdialysis in the prefrontal cortex and ventral hippocampus of freely moving rats. Subchronic effects of Lu AA21004 on extracellular 5-HT levels in the hippocampus and 5-HT transporter (5-HTT) occupancy were measured following a 3-day administration (5 mg/kg/day, sc, by osmotic minipumps). In vivo 5-HTT occupancy of Lu AA21004 following the 3-day administration was determined using 3H-MADAM as radioligand. Effects of Lu AA21004 on the 5-HT3 receptor were studied by measuring the Bezold-Jarisch-like reflex in rats. Antidepressant potential was assessed in the mouse forced swim and tail suspension tests, and anxiolytic potential was assessed using the rat conditioned fear and rat social interaction tests. The behavioural responses in the rat were correlated with 5-HTT occupancy levels by measuring ex vivo binding. Results: Lu AA21004 significantly increased extracellular 5-HT, NA, DA and ACh levels in a dose-dependent manner. After a 3-day administration, Lu AA21004 significantly increased extracellular 5-HT levels at approximately 40% 5-HTT occupancy. The microdialysis results support a profile of Lu AA21 004 that differs from current antidepressants. Lu AA21004 dosedependently inhibited the Bezold-Jarisch-like reflex [effective dose EDso = 0.1 mg/kg], demonstrating a 5-HT3 receptor antagonistic action ofLu AA21004 in vivo. Lu AA21004 produced dosedependent antidepressant-like effects in mice [minimal effective dose (MED) = 16 and 17mg/kg in the forced swim and tail suspension, respectively]. Lu AA21004 showed a significant and dose-dependent anxiolytic-like profile (MED 10 and 1.0mg/kg in the conditioned fear and social interaction tests, respectively) at low 5-HTT occupancy levels (approximately 45% and <5%, respectively). The selective 5-HT reuptake inhibitor, paroxetine was inactive in the conditioned fear test and the 5-HT and NA reuptake inhibitor, duloxetine and the 5-HT3 receptor antagonist, ondansetron were inactive in all tests of anxiolytic activity. Conclusions: Lu AA21004 affects brain levels of neurotransmitter systems assumed to be involved in the pathophysiology of mood disorders and shows robust antidepressant- and anxiolyticlike actions in preclinical models. This profile is different from other antidepressants, which may translate into a unique therapeutic profile.
1P.2.d.0181 Mechanisms contributing to the regulation of the different phases of neurogenesis by agomelatine A Soumier1, S. Lortet1, F. Masmejean 1, C. Gabriel2 , E. Mocae?, M. Millan3 , A Daszuta1 •. 1 CNRS - Universite de /a mediterranee, Cell interactions Neurodegeneration and Neurop/asticity Laboratory (IC2N)IBDML UMR-6216, Marseille Cedex 9, France; 3 IDR Servier, Research Department, Croissy, France
Objectives: Structural alterations such as reduced hippocampal volume, dendritic retraction and potential decreases in adult neurogenesis, as well as decreased levels of neurotrophic factors contribute to the pathogenesis of major depression. Agomelatine, a new antidepressant with melatonergic agonist and 5-HT2C antagonist properties, after chronic treatment, increases hippocampal granule cell proliferation and neurogenesis in the ventral hippocampus, both in basal and stressful conditions [1,2].
1P.2.d.0171 Pharmacological profile of Lu AA21004, a novel multi-target drug for the treatment of mood disorders A Mmk1 ., L.T. Brennum2 , S. Fallon3 , S. Bisulc03 , K. Frederiksen2 , B. Bang-Andersen2 , AB. Lassen2 , H. Zhong3 , C. Sanchez3 , T.B. Stensb012 . 1 H. Lundbeck A/S, Department of Neurophysi%gy, Copenhagen-Va/by, Denmark; 2 H. Lundbeck A/S, Research, Va/by-Copenhagen, Denmark; 3Lundbeck Research USA, Research, New Jersey, USA
Purpose of the study: Significant unmet needs in the treatment of depression and anxiety remain, despite the existence of several current treatment options. Lu AA21004 is a novel compound with a unique pharmacological profile. Lu AA21004 is a potent 5-HT3 receptor antagonist (h5-HT3A receptors: Kj =4.5 nM), 5-HTIA receptor agonist (h5-HTIA receptors: Kj = 15 nM) and 5-HT transporter inhibitor (h5-HTT ICso = 5.4 nM). The aim of the present research was to study the effects of Lu AA21004 on neurotransmitter levels in the brain and to test the compound in preclinical models predictive of anxiolytic- and antidepressant-like effects.
S439
Methods: The acute effects ofLu AA21004 (2.5-lOmg/kg, sc) on extracellular neurotransmitter [serotonin (5-HT), noradrenaline (NA), dopamine (DA), acetylcholine (ACh)] levels were measured by microdialysis in the prefrontal cortex and ventral hippocampus of freely moving rats. Subchronic effects of Lu AA21004 on extracellular 5-HT levels in the hippocampus and 5-HT transporter (5-HTT) occupancy were measured following a 3-day administration (5 mg/kg/day, sc, by osmotic minipumps). In vivo 5-HTT occupancy of Lu AA21004 following the 3-day administration was determined using 3H-MADAM as radioligand. Effects of Lu AA21004 on the 5-HT3 receptor were studied by measuring the Bezold-Jarisch-like reflex in rats. Antidepressant potential was assessed in the mouse forced swim and tail suspension tests, and anxiolytic potential was assessed using the rat conditioned fear and rat social interaction tests. The behavioural responses in the rat were correlated with 5-HTT occupancy levels by measuring ex vivo binding. Results: Lu AA21004 significantly increased extracellular 5-HT, NA, DA and ACh levels in a dose-dependent manner. After a 3-day administration, Lu AA21004 significantly increased extracellular 5-HT levels at approximately 40% 5-HTT occupancy. The microdialysis results support a profile of Lu AA21 004 that differs from current antidepressants. Lu AA21004 dosedependently inhibited the Bezold-Jarisch-like reflex [effective dose EDso = 0.1 mg/kg], demonstrating a 5-HT3 receptor antagonistic action ofLu AA21004 in vivo. Lu AA21004 produced dosedependent antidepressant-like effects in mice [minimal effective dose (MED) = 16 and 17mg/kg in the forced swim and tail suspension, respectively]. Lu AA21004 showed a significant and dose-dependent anxiolytic-like profile (MED 10 and 1.0mg/kg in the conditioned fear and social interaction tests, respectively) at low 5-HTT occupancy levels (approximately 45% and <5%, respectively). The selective 5-HT reuptake inhibitor, paroxetine was inactive in the conditioned fear test and the 5-HT and NA reuptake inhibitor, duloxetine and the 5-HT3 receptor antagonist, ondansetron were inactive in all tests of anxiolytic activity. Conclusions: Lu AA21004 affects brain levels of neurotransmitter systems assumed to be involved in the pathophysiology of mood disorders and shows robust antidepressant- and anxiolyticlike actions in preclinical models. This profile is different from other antidepressants, which may translate into a unique therapeutic profile.
1P.2.d.0181 Mechanisms contributing to the regulation of the different phases of neurogenesis by agomelatine A Soumier1, S. Lortet1, F. Masmejean 1, C. Gabriel2 , E. Mocae?, M. Millan3 , A Daszuta1 •. 1 CNRS - Universite de /a mediterranee, Cell interactions Neurodegeneration and Neurop/asticity Laboratory (IC2N)IBDML UMR-6216, Marseille Cedex 9, France; 3 IDR Servier, Research Department, Croissy, France
Objectives: Structural alterations such as reduced hippocampal volume, dendritic retraction and potential decreases in adult neurogenesis, as well as decreased levels of neurotrophic factors contribute to the pathogenesis of major depression. Agomelatine, a new antidepressant with melatonergic agonist and 5-HT2C antagonist properties, after chronic treatment, increases hippocampal granule cell proliferation and neurogenesis in the ventral hippocampus, both in basal and stressful conditions [1,2].