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P.1.c.013 Differential expression of BDNF mRNA in brain of rat after chronic lithium treatment
P.1.c Basic neuroscience – Neuropharmacology later. The total period of immobility during the 6-min testing period was recorded and data were assessed using the Student’s t test. All data were analyzed by one-way ANOVA and post-hoc comparisons for statistical significance were made by the Dunett’s test. Compaired with control-treated rats, withdrawn animals showed significant decreases in the percent number of entries onto open arms of the pluz-maze on the 24th hour (F 1.19 = 5.34; p < 0.03) and reduced vertical locomotor actitvity in optovarimex on the 96th h after the last diazepam injection (F1.19 = 12.29; p < 0.0025), indicating an anxiogenic response on withdrawal from diazepam. Calcium channel blockers verapamil (10 mg/kg, PO) and diltiazem (15 mg/kg PO) applied during the 21 – diazepam treatment and 1 h before testing significantly reversed the anxiogenic effects after diazepam withdrawal in the elevated plus-maze (F1.19 = 5.4; p < 0.03; F1.19 = 6.2; p < 0.03) respectively, and were ineffective in optovarimex. In the forced swimming test chronic administration of both diazepam and verapamil (F 1.19 = 8.92; p < 0.07) or diazepam and diltiazem (F 1.19 = 19.81; p < 0.0003) significantly decreased the duration of immobility as compared with withdrawn rats. Withdrawal of benzodiazepines is currently advised for millions long-term benzodiazepine users because of dobts about continued efficacy and risks of adverse effects. Adjuvant medication may occasionally be required for successful withdrawal strategy. Our present findings are consistent with earlier proposals that concurrent treatment with some calcium antagonists could reverse the increased anxiety after benzodiazepine withdrawal (Chug et al., 1992; Hitchcott et al., 1992). The possible neurochemical changes underlying in the effect of calcium blockers verapamil and diltiazem are discussed in the light of their possible serotonergic activity and relationship between serotonin and dopamine neurons. We suggest that chronic treatment with some L-type (verapamil) and T-type (diltiazem) calcium channel blockers may prove to be a promising strategy for preventing the development of benzodiazepine withdrawal-induced anxiety. References [1] Chugh Y, Saha N, Sankaranarayanan A, Sharma PL, 1992, Effect of peripheral administration of cinnarizine and verapamil on the abstinence syndrome in dizepam-dependent rats. Psychopharmacology 106(1), 127−30. [2] File SE, Andrews N, 1991, Low but not high doses of buspirone reduce the anxiogenic effects of diazepam withdrawal. Psychopharmacology 105, 578−82. [3] Hitchcott PK, Zharovsky A, File SE, 1992, Concurent treatment with verapamil prevents diazepam withdrawal-induced anxiety in the absence of altered calcium flux in cortical synaptosomes. Neuropharmacology 31(1), 55−60.
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reported. Brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor family, has multiple functions including a role in the promotion of neuronal survival and synaptic plasticity. A number of animal and human studies have suggested a function of BDNF in the pathogenesis of recurrent mood disorder. BDNF found to be low in depressed patient in anterior hippocampal sections of their postmortem brain. Moreover repeated stress results in a reduction in hippocampal BDNF. Lithium, the lightest monovalent cation of the alkali metals, acts as a mood-stabilizing agent and is widely used for the acute and prophylactic treatment of bipolar disorder and recurrent depression. Although precise action mechanism of lithium on recurrent mood disorder has not yet been elucidated, a number of evidences suggest that lithium may play a role through neuroprotecton [3]. Several mechanisms has proposed, including inactivation of NMDA receptor, decreased expression of p53 and Bax, and enhanced expression of Bcl2 or BDNF [2]. In this study we examined the effects of lithium on BDNF mRNA expression on various brain regions. Male Sprague Dawley rats, aged 8weeks with body weight of 230 g to 250 g were used. Rats were fed with regular rodent chow or 0.2% lithium carbonate-containing diet for 3weeks, and a bottle of saline was available for rats which reach the lithium concentration was 0.48±0.09 mmol/L (n = 9) in lithium fed rats. Cerebral cortex, hippocampus formation, striatum, midbrain and cerebellum were removed and subjected to SYBR Green I reverse transcriptionpolymerase chain reaction to quantify the mRNA expression in various brain regions. Lithium treatment increases BDNF mRNA in cerebral cortex, hippocampal formation, striatum, diencephalon and midbrain, but not in cerebellum. Also, we used fluorescence in situ hybridization to measure regional BDNF mRNA expression. In layer 5 of prefrontal cortex, CA1, CA3, CA4 and subgranular zone of hippocampus, substantia nigra, ventral striatum showed increased expression of BDNF mRNA in lithium treated group. These features suggest that lithium treatment increases the expression of BDNF mRNA in various brains regions considered to be involved in recurrent mood disorder. To our knowledge, this is the first report that showed the differential expression of BDNF mRNA in whole brain areas after chronic lithium treatment. Our result suggests that mood stabilizing effect of lithium may be through the region specific up-regulation of BDNF expression. References
P.1.c.013 Differential expression of BDNF mRNA in brain of rat after chronic lithium treatment
[1] Manji HK, Duman RS, 2001, Impairments of neuroplasticity and cellular resilience in severe mood disorders: implications for the development of novel therapeutics. Psychopharmacol Bull 35(2), 5−49. [2] Fukumoto T, Morinobu S, Okamoto Y, Kagaya A, Yamawaki S, 2001, Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain. Psychopharmacology 158(1), 100−6. [3] Kang HJ, Noh JS, Bae YS, Gwag BJ, 2003, Calcium-dependent prevention of neuronal apoptosis by lithium ion: essential role of phosphoinositide 3-kinase and phospholipase Cgamma. Mol Pharmacol 64(2), 228−34.
J.S. Noh1 ° , M.Y. Eu2 , Y.K. Chung1 , B.J. Gwag2 . 1 Ajou Universiy School of Medicine, Psychiatry, Suwon, South-Korea; 2 Ajou Universiy School of Medicine, Pharmacology, Suwon, South-Korea
P.1.c.014 The influence of prenatal administration of arginine-vasopressin on the postpound behaviour in white rats
Recurrent mood disorders, especially bipolar disorder, are lifethreatening clinical conditions which have been conceptualized as neurochemical disorders. But there are evidences demonstrating these devastating illnesses as neuropathologic disease. Reduction of volume, cell number and cell body size in prefrontal cortex, putamen, palidum, hippocampus and cingulated gyrus has been
O. Voskresenskaya ° , A. Kamensky, V. Golubovich. Lomonosov Moscow State University, Human and Animal Physiology, Moscow, Russia Introduction: Arginine-vasopressin (AVP) binding sites transiently expressed in the brain of fetal and infant rat probably
S249
reported. Brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor family, has multiple functions including a role in the promotion of neuronal survival and synaptic plasticity. A number of animal and human studies have suggested a function of BDNF in the pathogenesis of recurrent mood disorder. BDNF found to be low in depressed patient in anterior hippocampal sections of their postmortem brain. Moreover repeated stress results in a reduction in hippocampal BDNF. Lithium, the lightest monovalent cation of the alkali metals, acts as a mood-stabilizing agent and is widely used for the acute and prophylactic treatment of bipolar disorder and recurrent depression. Although precise action mechanism of lithium on recurrent mood disorder has not yet been elucidated, a number of evidences suggest that lithium may play a role through neuroprotecton [3]. Several mechanisms has proposed, including inactivation of NMDA receptor, decreased expression of p53 and Bax, and enhanced expression of Bcl2 or BDNF [2]. In this study we examined the effects of lithium on BDNF mRNA expression on various brain regions. Male Sprague Dawley rats, aged 8weeks with body weight of 230 g to 250 g were used. Rats were fed with regular rodent chow or 0.2% lithium carbonate-containing diet for 3weeks, and a bottle of saline was available for rats which reach the lithium concentration was 0.48±0.09 mmol/L (n = 9) in lithium fed rats. Cerebral cortex, hippocampus formation, striatum, midbrain and cerebellum were removed and subjected to SYBR Green I reverse transcriptionpolymerase chain reaction to quantify the mRNA expression in various brain regions. Lithium treatment increases BDNF mRNA in cerebral cortex, hippocampal formation, striatum, diencephalon and midbrain, but not in cerebellum. Also, we used fluorescence in situ hybridization to measure regional BDNF mRNA expression. In layer 5 of prefrontal cortex, CA1, CA3, CA4 and subgranular zone of hippocampus, substantia nigra, ventral striatum showed increased expression of BDNF mRNA in lithium treated group. These features suggest that lithium treatment increases the expression of BDNF mRNA in various brains regions considered to be involved in recurrent mood disorder. To our knowledge, this is the first report that showed the differential expression of BDNF mRNA in whole brain areas after chronic lithium treatment. Our result suggests that mood stabilizing effect of lithium may be through the region specific up-regulation of BDNF expression. References
P.1.c.013 Differential expression of BDNF mRNA in brain of rat after chronic lithium treatment
[1] Manji HK, Duman RS, 2001, Impairments of neuroplasticity and cellular resilience in severe mood disorders: implications for the development of novel therapeutics. Psychopharmacol Bull 35(2), 5−49. [2] Fukumoto T, Morinobu S, Okamoto Y, Kagaya A, Yamawaki S, 2001, Chronic lithium treatment increases the expression of brain-derived neurotrophic factor in the rat brain. Psychopharmacology 158(1), 100−6. [3] Kang HJ, Noh JS, Bae YS, Gwag BJ, 2003, Calcium-dependent prevention of neuronal apoptosis by lithium ion: essential role of phosphoinositide 3-kinase and phospholipase Cgamma. Mol Pharmacol 64(2), 228−34.
J.S. Noh1 ° , M.Y. Eu2 , Y.K. Chung1 , B.J. Gwag2 . 1 Ajou Universiy School of Medicine, Psychiatry, Suwon, South-Korea; 2 Ajou Universiy School of Medicine, Pharmacology, Suwon, South-Korea
P.1.c.014 The influence of prenatal administration of arginine-vasopressin on the postpound behaviour in white rats
Recurrent mood disorders, especially bipolar disorder, are lifethreatening clinical conditions which have been conceptualized as neurochemical disorders. But there are evidences demonstrating these devastating illnesses as neuropathologic disease. Reduction of volume, cell number and cell body size in prefrontal cortex, putamen, palidum, hippocampus and cingulated gyrus has been
O. Voskresenskaya ° , A. Kamensky, V. Golubovich. Lomonosov Moscow State University, Human and Animal Physiology, Moscow, Russia Introduction: Arginine-vasopressin (AVP) binding sites transiently expressed in the brain of fetal and infant rat probably