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P.2.h.002 Effects of the multimodal antidepressant Lu AA21004 on rat synaptic and cellular hippocampal plasticity and memory recognition
P.3.a. Psychotic disorders and antipsychotics − Psychotic disorders (clinical) conditioning that were induced by repeated LPS administration. Moreover, we observed that chronic treatment with Cit prevented LPS-induced reactive gliosis, prevented altered synaptic plasticity, and reduced aberrant proliferative activity within the dentate gyrus of adult mouse hippocampus. We found that the population size of BrdU-positive cells that express markers of mature neurons was increased in the Cit-treated animals compared to LPS-treated animals and the number of cells expressing markers for glial cells was reduced in Cit-treated group compared to LPS-treated mice. These findings suggest that citalopram has therapeutic potential for treating pathologies that are associated with inflammation and altered neuroplasticity. References [1] O’Sullivan JB, Ryan KM, Curtin NM, Harkin A, Connor TJ., 2009. Noradrenaline reuptake inhibitors limit neuroinflammation in rat cortex following a systemic inflammatory challenge: implications for depression and neurodegeneration. Int J Neuropsychopharmacol. 12, 687−99. [2] Leonard BE., 2010. The concept of depression as a dysfunction of the immune system. Curr Immunol Rev 3, 205–212. [3] Hashioka S., 2011. Antidepressants and neuroinflammation: Can antidepressants calm glial rage down? Mini Rev Med Chem 7, 555–564.
P.2.h.002 Effects of the multimodal antidepressant Lu AA21004 on rat synaptic and cellular hippocampal plasticity and memory recognition N. Haddjeri1 ° , A. Eti´evant1 , A. Pehrson2 , C. S´anchez2 , C. B´etry1 1 Universit´e Claude Bernard, Inserm Laboratory of Neuropharmacology, Lyon C´edex 08, France; 2 Lundbeck Research USA, Neuropharmacology, Paramus NJ, USA Purpose: Depression is frequently associated with cognitive disturbances including memory, executive control and affective processing [1]. Thus, there is an urgent need to acquire effective antidepressants with pro-cognitive properties. Lu AA21004 is a multimodal investigational antidepressant that functions as a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the 5-HT transporter in vitro [2], and demonstrated antidepressant efficacy in a recent clinical study [3]. Given its original pharmacological profile, the present study was undertaken to determine whether administration of Lu AA21004 modified several in and ex vivo preclinical parameters involved in cognitive processing. Methods: Field excitatory postsynaptic potentials (fEPSP) were recorded in the CA1 area of dorsal hippocampus of rats anaesthetized with urethane before and after high frequency stimulation (HFS) of the Schaffer’s collaterals. Control, 5-HT depleted rats were given the irreversible inhibitor of tryptophan hydroxylase PCPA (3x100 mg/kg, i.p.). Stressed rats were placed on an elevated platform for 30 minutes before anaesthesia. Using a 24 h retention interval, the novel object recognition (NOR) test was used to evaluate episodic memory. The NOR task was performed in a plexiglass Y-maze apparatus and is based on the natural propensity of rats to explore novelty in their environment. More specifically, rodents are able to discriminate between a novel and a previously seen (i.e. familiar) object. Finally, using osmotic minipumps, the effects of sustained administrations of Lu AA21004 and the SSRI fluoxetine on hippocampal cell proliferation were measured by BrdU immunohistochemistry. Results: In control rats, HFS provoked a stable long term potentiation (LTP) of ~30%. The acute administration Lu AA21004
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(10 mg/kg, i.p.) did not alter fEPSP amplitude but reduced hippocampal LTP induction to ~10%. Interestingly, Lu AA21004 pre-treatment prevented the suppressant effect of stress on hippocampal LTP induction but not the effect of 5-HT depletion. In the NOR test, similarly to the prototypical pro-cognitive agent Aricept (1 mg/kg, i.p.), the acute administration of Lu AA21004 (10 mg/kg, i.p.) increased the time spent exploring the novel object during the retention test (index of recognition of ~40% versus ~10% for controls) and this effect was partly prevented by the selective 5-HT3 receptor agonist SR57227 (1 mg/kg, i.p.) and the selective 5-HT7 receptor agonist AS19 (5 mg/kg, i.p.). Finally, Lu AA21004 (5 mg/kg/day, s.c.) induced an increase of cell proliferation in the dentate gyrus after 1, 3 and 14 days of treatment, whereas at least 2 weeks of treatment with fluoxetine (10 mg/kg/day, s.c.) were necessary to significantly enhance hippocampal cell proliferation. Conclusion: Lu AA21004 produced an effect on LTP similar to that of serotonergic antidepressants. However, it significantly prevented the suppressant effect of acute stress but not of 5-HT depletion. Lu AA21004 also enhanced episodic memory, an effect mediated, at least part, by its 5-HT3/ 7 receptor antagonism. Finally, Lu AA21004 induced a surprisingly rapid increase of hippocampal cell proliferation. References [1] Clark, L., Chamberlain, S.R. and Sahakian B.J., 2009 Neurocognitive mechanisms in depression: implications for treatment. Annu Rev Neurosci 32, 57−74. [2] Bang-Andersen, B., et al., 2011 Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem 54: 3206–3221. [3] Alvarez, E., et al., 2011 A double-blind, randomized, placebocontrolled, active reference study of Lu AA21004 in patients with major depressive disorder. Int J Neuropsychopharmacol doi: 10.1017/ S1461145711001027. Disclosure statement: This paper is financially supported by a grant from Lundbeck A/S and Takeda.
P.3.a. Psychotic disorders and antipsychotics − Psychotic disorders (clinical) P.3.a.001 Sex differences in early adolescent functioning among persons later hospitalised for schizophrenia V. Ullman Zerem1 ° , S. Levine2 , J. Rabinowitz3 1 Ashkelon academic college, social work, Ashkelon, Israel; 2 University of Haifa, public health, Haifa, Israel; 3 Bar Ilan University, social work, Ramat Gan, Israel Background: Late adolescent premorbid deficits are evident in behavior and cognition in schizophrenia. Epidemiological population-based research is yet to examine premorbid cognitive, behavioral and nonacademic functioning in the early teenage years in schizophrenia. Studies consistently show that compared with women men have an earlier age of onset, and poorer outcomes in schizophrenia. Also compared with females, males have more pooerer premorbid functioning and an earlier age of onset [1,3]. Studies of cognitive functioning have found lower cognitive functioning among males who later in life developed schizophrenia versus females. Population-based research of the late teenage
P.2.h.002 Effects of the multimodal antidepressant Lu AA21004 on rat synaptic and cellular hippocampal plasticity and memory recognition N. Haddjeri1 ° , A. Eti´evant1 , A. Pehrson2 , C. S´anchez2 , C. B´etry1 1 Universit´e Claude Bernard, Inserm Laboratory of Neuropharmacology, Lyon C´edex 08, France; 2 Lundbeck Research USA, Neuropharmacology, Paramus NJ, USA Purpose: Depression is frequently associated with cognitive disturbances including memory, executive control and affective processing [1]. Thus, there is an urgent need to acquire effective antidepressants with pro-cognitive properties. Lu AA21004 is a multimodal investigational antidepressant that functions as a 5-HT3 and 5-HT7 receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and inhibitor of the 5-HT transporter in vitro [2], and demonstrated antidepressant efficacy in a recent clinical study [3]. Given its original pharmacological profile, the present study was undertaken to determine whether administration of Lu AA21004 modified several in and ex vivo preclinical parameters involved in cognitive processing. Methods: Field excitatory postsynaptic potentials (fEPSP) were recorded in the CA1 area of dorsal hippocampus of rats anaesthetized with urethane before and after high frequency stimulation (HFS) of the Schaffer’s collaterals. Control, 5-HT depleted rats were given the irreversible inhibitor of tryptophan hydroxylase PCPA (3x100 mg/kg, i.p.). Stressed rats were placed on an elevated platform for 30 minutes before anaesthesia. Using a 24 h retention interval, the novel object recognition (NOR) test was used to evaluate episodic memory. The NOR task was performed in a plexiglass Y-maze apparatus and is based on the natural propensity of rats to explore novelty in their environment. More specifically, rodents are able to discriminate between a novel and a previously seen (i.e. familiar) object. Finally, using osmotic minipumps, the effects of sustained administrations of Lu AA21004 and the SSRI fluoxetine on hippocampal cell proliferation were measured by BrdU immunohistochemistry. Results: In control rats, HFS provoked a stable long term potentiation (LTP) of ~30%. The acute administration Lu AA21004
S303
(10 mg/kg, i.p.) did not alter fEPSP amplitude but reduced hippocampal LTP induction to ~10%. Interestingly, Lu AA21004 pre-treatment prevented the suppressant effect of stress on hippocampal LTP induction but not the effect of 5-HT depletion. In the NOR test, similarly to the prototypical pro-cognitive agent Aricept (1 mg/kg, i.p.), the acute administration of Lu AA21004 (10 mg/kg, i.p.) increased the time spent exploring the novel object during the retention test (index of recognition of ~40% versus ~10% for controls) and this effect was partly prevented by the selective 5-HT3 receptor agonist SR57227 (1 mg/kg, i.p.) and the selective 5-HT7 receptor agonist AS19 (5 mg/kg, i.p.). Finally, Lu AA21004 (5 mg/kg/day, s.c.) induced an increase of cell proliferation in the dentate gyrus after 1, 3 and 14 days of treatment, whereas at least 2 weeks of treatment with fluoxetine (10 mg/kg/day, s.c.) were necessary to significantly enhance hippocampal cell proliferation. Conclusion: Lu AA21004 produced an effect on LTP similar to that of serotonergic antidepressants. However, it significantly prevented the suppressant effect of acute stress but not of 5-HT depletion. Lu AA21004 also enhanced episodic memory, an effect mediated, at least part, by its 5-HT3/ 7 receptor antagonism. Finally, Lu AA21004 induced a surprisingly rapid increase of hippocampal cell proliferation. References [1] Clark, L., Chamberlain, S.R. and Sahakian B.J., 2009 Neurocognitive mechanisms in depression: implications for treatment. Annu Rev Neurosci 32, 57−74. [2] Bang-Andersen, B., et al., 2011 Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem 54: 3206–3221. [3] Alvarez, E., et al., 2011 A double-blind, randomized, placebocontrolled, active reference study of Lu AA21004 in patients with major depressive disorder. Int J Neuropsychopharmacol doi: 10.1017/ S1461145711001027. Disclosure statement: This paper is financially supported by a grant from Lundbeck A/S and Takeda.
P.3.a. Psychotic disorders and antipsychotics − Psychotic disorders (clinical) P.3.a.001 Sex differences in early adolescent functioning among persons later hospitalised for schizophrenia V. Ullman Zerem1 ° , S. Levine2 , J. Rabinowitz3 1 Ashkelon academic college, social work, Ashkelon, Israel; 2 University of Haifa, public health, Haifa, Israel; 3 Bar Ilan University, social work, Ramat Gan, Israel Background: Late adolescent premorbid deficits are evident in behavior and cognition in schizophrenia. Epidemiological population-based research is yet to examine premorbid cognitive, behavioral and nonacademic functioning in the early teenage years in schizophrenia. Studies consistently show that compared with women men have an earlier age of onset, and poorer outcomes in schizophrenia. Also compared with females, males have more pooerer premorbid functioning and an earlier age of onset [1,3]. Studies of cognitive functioning have found lower cognitive functioning among males who later in life developed schizophrenia versus females. Population-based research of the late teenage