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P.2.d.016 Effects of long-term treatment with bupropion on the firing activity of serotonin and norepinephrine neurons
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P.2.d Affective disorders and antidepressants – Antidepressants (basic)
for respiration. Freezing behaviour as an index of conditioned fear in the rat (Fanselow and Bolles, 1979) was scored in a blinded fashion during the 2-min test period. Total accumulated freezing time (total seconds spent freezing during each period) was used as a measure for contextual fear memory. Escitalopram at 1 mg/kg (but not at 0.5 or 5 mg/kg), given to rats 30 min before acquisition, significantly increased the time spent freezing during the test (56.46±6.79%, n = 10, versus 27.76±6.48%, n = 10, in the vehicle-treated animals, p < 0.05). Escitalopram (at any dose tested) did not affect freezing behaviour before the presentation of the foot shock (during fear acquisition). In vivo microdialysis demonstrated that escitalopram (1 mg/kg, sc) increases extracellular 5-HT in the ventral hippocampus of freely moving rats. Investigations combining selective 5-HT receptors antagonists and escitalopram are ongoing to understand the mechanisms underlying escitalopram effects and to obtain knowledge on which 5-HT receptor subtypes mediate these effects. In conclusion, the present study revealed that escitalopram after acute administration enhances fear memory. These findings might contribute to the understanding of the cognitive effects of escitalopram for the treatment of anxiety and depression. Liliana P. Montezinho was supported by F.C.T. (SFRH/BPD/ 18389/2004) grant References [1] Fanselow MS, Bolles RC, 1979, Naloxone and shock-elicited freezing in the rat. J Comp Physiol Psychol 93, 736–744.
P.2.d.015 The effects of desvenlafaxine succinate and paroxetine on the pharmacokinetics of desipiramine in healthy adults A. Patroneva ° , A.I. Nichols, P. Fatato, M. Shenouda2 , J. Paul, R.D. Pedersen, Q. Jiang, S. Ahmed. Wyeth Research, Global Medical Affairs, Philadelphia, USA Objective: To evaluate the effect of multiple doses of desvenlafaxine succinate (DVS) and paroxetine on the pharmacokinetics of a single dose of desipiramine in healthy adults. Methods: This open-label, randomized crossover inpatient study was conducted in 19 healthy adults aged 21 to 50 years. The study consisted of 4 periods. In period 1, a single 50-mg dose of desipiramine was administered, followed by 120 hours of sampling. In period 2, desvenlafaxine succinate or paroxetine were administered alone on specific treatment days and coadministered with desipiramine on other specific treatment days. Period 3 was a washout phase; in period 4, desvenlafaxine succinate or paroxetine were administered alone on specific treatment days and coadministered with desipiramine on other specific treatment days. Desvenlafaxine succinate is a weak inhibitor of CYP2D6 activity and has no inhibitory effects on other cytochrome P450s. Paroxetine is a potent CYP2D6 inhibitor and was included in the study as a positive control. Plasma was assayed by HPLC MS/MS for determination of desipiramine and 2-OH desipiramine concentrations. Least squares geometric mean ratios of combination treatment (desipiramine with DVS SR or with paroxetine) to the reference (desipiramine alone) were calculated for desipiramine and 2-OH desipiramine AUC and Cmax. Comparisons between treatment groups (DVS vs paroxetine) were calculated with a 2-period crossover analysis of variance based on logarithms for AUC and Cmax of combination therapy to the reference. Results: There was a statistically significant difference (p < 0.001) between the effect of the 2 treatments on desipiramine
AUC, desipiramine Cmax and 2-OH desipiramine Cmax. Coadministration of daily doses of DVS with desipramine produced minor increases in desipiramine AUC (36%) and Cmax (30%). Cmax for 2-OH desipramine was similar, and AUC increased 16% during coadministration of desipiramine and desvenlafaxine succinate. Desipiramine AUC and Cmax increased 419% and 90%, respectively, following daily dosing with paroxetine 20 mg. Cmax and AUC for 2-OH desipiramine decreased 82% and 18% during coadministration of desipiramine and paroxetine. The results of this study indicate that coadministration of the CYP2D6 substrate desipiramine with 100-mg daily doses of desvenlafaxine succinate resulted in approximately similar exposure to desipiramine and 2-hydroxydesipiramine. This contrasts with the sizeable changes observed in desipiramine pharmacokinetics after coadministration with paroxetine. Of the 20 patients genotyped, a total of 20 (80%) were predicted to exhibit an extensive metabolizer phenotype. A total of 3 patients (15%) were predicted to exhibit an intermediate metabolizer phenotype, and 1 patient (0.5%) was predicted to possess a poor metabolizer phenotype. No patients were predicted to exhibit the ultrarapid metabolizer phenotype. Treatment emergent adverse events included nausea, headache, diarrhea, and dizziness. Conclusion: Daily administration of 100 mg desvenlafaxine succinate shows only weak inhibition of the pharmacokinetics of desipiramine AUC ( ↑ 36%), indicating that it will have minimal to no interaction with other CYP2D6 substrates. In contrast, coadministration of paroxetine resulted in strong inhibition in desipiramine AUC ( ↑ 419%). References [1] Spina E, Scordo MG, D’Arrigo C, 2003, Metabolic drug interactions with new psychotropic agents. Fundamental Clin. Pharm 17, 517–538. [2] Deecher DC, Beyer CE, Johnston G, 2006, Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor. J. Pharmacol. Exp. Ther 318, 657–665.
P.2.d.016 Effects of long-term treatment with bupropion on the firing activity of serotonin and norepinephrine neurons M. El Mansari1 ° , R. Ghanbari1 , S. Janssen2 , P. Blier1 . 1 University of Ottawa Institute of Mental Health Research, 1145 Carling Avenue, Ottawa, Canada; 2 University of Florida, Neuroscience, Gainesville, USA Introduction: Bupropion is widely used in the treatment of depression and as an anti-craving medication for the cessation of tobacco smoking. Despite its weak affinity for norepinephrine (NE) and dopamine (DA), bupropion is believed to work as a NE and DA reuptake inhibitor. However, a 2-day treatment with bupropion decreases the firing rate of NE neurons, increases that of serotonin (5-HT) neurons and leaves unchanged that of ventral tegmental area DA neurons, in anesthetized rats [1]. The present in vivo electrophysiological study was conducted to examine the effects of prolonged bupropion administration (2, 7, 14 days) on the firing rate of locus coeuruleus (LC) NE neurons and raphe dorsalis (RD) 5-HT neurons as well as the sensitivity of a2-adrenoceptor and 5-HT1A autoreceptor in those respective structures. Methods: Male Sprague Dawley rats were anesthetized with chloral hydrate and mounted in stereotaxic frame. LC and RD neurons were recorded extracellularly using single-barreled micropipettes filled with 2 M NaCl solution. Bupropion was administered subcutaneously at a dose of 30 mg/kg, and treated rats
P.2.d Affective disorders and antidepressants – Antidepressants (basic) were tested with minipumps in place. Control rats were treated with water. Results: In LC, the firing rate of NE neurons was significantly attenuated after 2 days treatment, as previously reported [1], but recovered progressively after 7 and 14 days of treatment. The sensitivity of somatodendritic a2-adrenergic autoreceptor was then assessed in rats treated for 14 days. The suppressant effect of clonidine on the firing activity of NE neurons was significantly attenuated by 82% in rats treated with bupropion for 14 days. Sustained bupropion administration decreased the firing rate of NE neurons due to an increased activation of their inhibitory somatodendritic a2-adrenoceptors. However, prolongation of bupropion treatment from 2 to 14 days desensitized a2-adrenoceptors, presumably due to a sustained increase in synaptic NE concentration, and ultimately resulted in the normalization of LC firing activity. In RD, the firing rate of 5-HT neurons was significantly increased after 2 days treatment. Assessment of the 5-HT1A autoreceptor showed that the suppressant effect of LSD was diminished by 88% in RD, indicating a desensitization of this autoreceptor. The latter may underlie the rapid and sustained increase in the firing rate of 5-HT neurons obtained as early as two days after starting bupropion. Conclusion: The present results confirm and extend previous findings indicating that bupropion has the capacity to increase synaptic availability of NE. This effect of bupropion would be attributable mainly to an enhancement of NE release and not to reuptake inhibition [1]. This contention is based essentially on the observation that NE reuptake blockers leave unaltered the firing rate of 5-HT neurons. The gradual recovery of NE in the presence of the sustained increase in 5-HT neuronal firing may be explained in part the delayed onset of action of bupropion in major depression. References [1] Dong J, Blier P, 2001, Modification of norepinephrine and serotonin, but not dopamine, neuron firing by sustained bupropion treatment. Psychopharmacol 155, 52−57.
P.2.d.017 Behavioral and molecular effects of repeated treatment with citalopram alone or combined with memantine in rats A. Tamburella ° , V. Micale, M. Zammataro, F. Drago. University of Catania, Dept. of Experimental and Clinical Pharmacology, Catania, Italy Hippocampus is considered as a target for antidepressant drugs, since it is one of the major brain areas involved in emotional processes and in the pathogenesis of depression. Preclinical studies show a decreased expression in this area of the nuclear transcription factor cAMP response element binding protein (CREB), considered as a typical sign of impaired neural plasticity in depression, influenced by drugs affecting brain monoamine systems. Thus, the therapeutic effect of several classes of antidepressants is related to a regulation of hippocampal levels of adenylyl cyclase and to the over-expression of this protein (Thome et al., 2000), leading to improved behavioral performance in animal models of depression (Chen et al., 2001). Selective serotonin (5-HT) reuptake inhibitors (SSRIs) have long gained extensive clinical use and are drugs of choice for the treatment of depression. Recently, the glutamatergic system has benn involved in depression. In particular, NMDA receptor antagonists such as the uncompetitive antagonist, memantine (MEM) have been shown to exert antidepressive-like effects in animal models (Rogoz et al., 2002).
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The aim of the present study was to evaluate the association of MEM to the SSRI, citalopram on the antidepressive-like effects of the latter in the forced swimming test (FST) and in the expression of CREB protein in hippocampus of rats as assessed by Western Blot analysis. Male Wistar rats were treated i.p. for 14 days with citalopram (8 and 16 mg/kg/day), MEM (2.5 mg/kg) or vehicle. Citalopram 8 mg/kg did not modify the immobility time of rats compared to vehicle. Only at the dose of 16 mg/kg, citalopram treated rats exhibited a better behavioral performance in FST than vehicletreated controls. MEM did not show any change in the reduction of the immobility time when administered alone. When coinjected to citalopram 8 or 16 mg/kg, MEM 2.5 mg/kg improved the behavioral performance of rats in FST (P < 0.05; P < 0.01). Western blot analysis of hippocampal homogenates showed that CREB protein expression is significantly higher in rats treated with citalopram at the dose of 16 mg/kg/day (P < 0.01), but not at the dose of 8 mg/kg/day, in comparison to vehicle-injected controls. Memantine-treated rats also failed to show any change in the hippocampal CREB expression. However, MEM co-administered with both doses of citalopram, induced an increased CREB protein expression as compared to vehicle (P < 0.05; P < 0.01). These findings demonstrate that inefficacious doses of citalopram and MEM, given in combination, are effective in exerting antidepressive effects, improving performances of rats tested in in FST. The combination also induced a CREB protein overexpression, that is recognized as a typical effect of antidepressants, suggesting that co-administration of MEM and citalopram may be useful to improve behavior and to enhance neural plasticity that usually follows chronic antidepressant treatment in rats hippocampus. References [1] Chen ACH, Shirayama Y, Shin KH, Neve RL, Duman RS, 2001, Expression of cAMP element binding protein (CREB) in hippocampus produces an antidepressant effect. Biol Psychiatry 49, 753–762. [2] Thome J, Sakai N, Shin K-H, Steffen C, Zang Y-J, Impey S, Storm D, Duman RS, 2000, cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment. J Neurosci 20, 4030–4036. [3] Rog´oz Z, Skuza G, Maj J, Danysz W, 2002, Synergistic effect of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rats. Neuropharmacology 42, 1024– 1030.
P.2.d.018 Effects from vagus nerve stimulation on rat hippocampal progenitor proliferation D. Revesz ° , M. Tjernstr¨om, E. Ben-Menachem, T. Thorlin. Institute of Clinical Neuroscience, Neurology, G¨oteborg, Sweden Purpose of the study: The birth of new neurons from neuronal stem cells, the process called neurogenesis, has been seen in adult brains from both rodents and humans. The process is especially prominent in the hippocampus, which is involved in mood and memory functions and epilepsy. A new hypothesis for the development of depression in humans has been formed over the last few years, which includes neurogenesis as a factor of importance in the depressive disease: Reduction of neurogenesis in the hippocampus is a causality factor in the generation of depression and stimulated neurogenesis is part of the recovery process from the depressive state (Jacobs et al., 2000). VNS therapy, which has been used successfully for many years in the treatment of epilepsy (BenMenachem, 2002), was early on in its development noted to
P.2.d Affective disorders and antidepressants – Antidepressants (basic)
for respiration. Freezing behaviour as an index of conditioned fear in the rat (Fanselow and Bolles, 1979) was scored in a blinded fashion during the 2-min test period. Total accumulated freezing time (total seconds spent freezing during each period) was used as a measure for contextual fear memory. Escitalopram at 1 mg/kg (but not at 0.5 or 5 mg/kg), given to rats 30 min before acquisition, significantly increased the time spent freezing during the test (56.46±6.79%, n = 10, versus 27.76±6.48%, n = 10, in the vehicle-treated animals, p < 0.05). Escitalopram (at any dose tested) did not affect freezing behaviour before the presentation of the foot shock (during fear acquisition). In vivo microdialysis demonstrated that escitalopram (1 mg/kg, sc) increases extracellular 5-HT in the ventral hippocampus of freely moving rats. Investigations combining selective 5-HT receptors antagonists and escitalopram are ongoing to understand the mechanisms underlying escitalopram effects and to obtain knowledge on which 5-HT receptor subtypes mediate these effects. In conclusion, the present study revealed that escitalopram after acute administration enhances fear memory. These findings might contribute to the understanding of the cognitive effects of escitalopram for the treatment of anxiety and depression. Liliana P. Montezinho was supported by F.C.T. (SFRH/BPD/ 18389/2004) grant References [1] Fanselow MS, Bolles RC, 1979, Naloxone and shock-elicited freezing in the rat. J Comp Physiol Psychol 93, 736–744.
P.2.d.015 The effects of desvenlafaxine succinate and paroxetine on the pharmacokinetics of desipiramine in healthy adults A. Patroneva ° , A.I. Nichols, P. Fatato, M. Shenouda2 , J. Paul, R.D. Pedersen, Q. Jiang, S. Ahmed. Wyeth Research, Global Medical Affairs, Philadelphia, USA Objective: To evaluate the effect of multiple doses of desvenlafaxine succinate (DVS) and paroxetine on the pharmacokinetics of a single dose of desipiramine in healthy adults. Methods: This open-label, randomized crossover inpatient study was conducted in 19 healthy adults aged 21 to 50 years. The study consisted of 4 periods. In period 1, a single 50-mg dose of desipiramine was administered, followed by 120 hours of sampling. In period 2, desvenlafaxine succinate or paroxetine were administered alone on specific treatment days and coadministered with desipiramine on other specific treatment days. Period 3 was a washout phase; in period 4, desvenlafaxine succinate or paroxetine were administered alone on specific treatment days and coadministered with desipiramine on other specific treatment days. Desvenlafaxine succinate is a weak inhibitor of CYP2D6 activity and has no inhibitory effects on other cytochrome P450s. Paroxetine is a potent CYP2D6 inhibitor and was included in the study as a positive control. Plasma was assayed by HPLC MS/MS for determination of desipiramine and 2-OH desipiramine concentrations. Least squares geometric mean ratios of combination treatment (desipiramine with DVS SR or with paroxetine) to the reference (desipiramine alone) were calculated for desipiramine and 2-OH desipiramine AUC and Cmax. Comparisons between treatment groups (DVS vs paroxetine) were calculated with a 2-period crossover analysis of variance based on logarithms for AUC and Cmax of combination therapy to the reference. Results: There was a statistically significant difference (p < 0.001) between the effect of the 2 treatments on desipiramine
AUC, desipiramine Cmax and 2-OH desipiramine Cmax. Coadministration of daily doses of DVS with desipramine produced minor increases in desipiramine AUC (36%) and Cmax (30%). Cmax for 2-OH desipramine was similar, and AUC increased 16% during coadministration of desipiramine and desvenlafaxine succinate. Desipiramine AUC and Cmax increased 419% and 90%, respectively, following daily dosing with paroxetine 20 mg. Cmax and AUC for 2-OH desipiramine decreased 82% and 18% during coadministration of desipiramine and paroxetine. The results of this study indicate that coadministration of the CYP2D6 substrate desipiramine with 100-mg daily doses of desvenlafaxine succinate resulted in approximately similar exposure to desipiramine and 2-hydroxydesipiramine. This contrasts with the sizeable changes observed in desipiramine pharmacokinetics after coadministration with paroxetine. Of the 20 patients genotyped, a total of 20 (80%) were predicted to exhibit an extensive metabolizer phenotype. A total of 3 patients (15%) were predicted to exhibit an intermediate metabolizer phenotype, and 1 patient (0.5%) was predicted to possess a poor metabolizer phenotype. No patients were predicted to exhibit the ultrarapid metabolizer phenotype. Treatment emergent adverse events included nausea, headache, diarrhea, and dizziness. Conclusion: Daily administration of 100 mg desvenlafaxine succinate shows only weak inhibition of the pharmacokinetics of desipiramine AUC ( ↑ 36%), indicating that it will have minimal to no interaction with other CYP2D6 substrates. In contrast, coadministration of paroxetine resulted in strong inhibition in desipiramine AUC ( ↑ 419%). References [1] Spina E, Scordo MG, D’Arrigo C, 2003, Metabolic drug interactions with new psychotropic agents. Fundamental Clin. Pharm 17, 517–538. [2] Deecher DC, Beyer CE, Johnston G, 2006, Desvenlafaxine succinate: A new serotonin and norepinephrine reuptake inhibitor. J. Pharmacol. Exp. Ther 318, 657–665.
P.2.d.016 Effects of long-term treatment with bupropion on the firing activity of serotonin and norepinephrine neurons M. El Mansari1 ° , R. Ghanbari1 , S. Janssen2 , P. Blier1 . 1 University of Ottawa Institute of Mental Health Research, 1145 Carling Avenue, Ottawa, Canada; 2 University of Florida, Neuroscience, Gainesville, USA Introduction: Bupropion is widely used in the treatment of depression and as an anti-craving medication for the cessation of tobacco smoking. Despite its weak affinity for norepinephrine (NE) and dopamine (DA), bupropion is believed to work as a NE and DA reuptake inhibitor. However, a 2-day treatment with bupropion decreases the firing rate of NE neurons, increases that of serotonin (5-HT) neurons and leaves unchanged that of ventral tegmental area DA neurons, in anesthetized rats [1]. The present in vivo electrophysiological study was conducted to examine the effects of prolonged bupropion administration (2, 7, 14 days) on the firing rate of locus coeuruleus (LC) NE neurons and raphe dorsalis (RD) 5-HT neurons as well as the sensitivity of a2-adrenoceptor and 5-HT1A autoreceptor in those respective structures. Methods: Male Sprague Dawley rats were anesthetized with chloral hydrate and mounted in stereotaxic frame. LC and RD neurons were recorded extracellularly using single-barreled micropipettes filled with 2 M NaCl solution. Bupropion was administered subcutaneously at a dose of 30 mg/kg, and treated rats
P.2.d Affective disorders and antidepressants – Antidepressants (basic) were tested with minipumps in place. Control rats were treated with water. Results: In LC, the firing rate of NE neurons was significantly attenuated after 2 days treatment, as previously reported [1], but recovered progressively after 7 and 14 days of treatment. The sensitivity of somatodendritic a2-adrenergic autoreceptor was then assessed in rats treated for 14 days. The suppressant effect of clonidine on the firing activity of NE neurons was significantly attenuated by 82% in rats treated with bupropion for 14 days. Sustained bupropion administration decreased the firing rate of NE neurons due to an increased activation of their inhibitory somatodendritic a2-adrenoceptors. However, prolongation of bupropion treatment from 2 to 14 days desensitized a2-adrenoceptors, presumably due to a sustained increase in synaptic NE concentration, and ultimately resulted in the normalization of LC firing activity. In RD, the firing rate of 5-HT neurons was significantly increased after 2 days treatment. Assessment of the 5-HT1A autoreceptor showed that the suppressant effect of LSD was diminished by 88% in RD, indicating a desensitization of this autoreceptor. The latter may underlie the rapid and sustained increase in the firing rate of 5-HT neurons obtained as early as two days after starting bupropion. Conclusion: The present results confirm and extend previous findings indicating that bupropion has the capacity to increase synaptic availability of NE. This effect of bupropion would be attributable mainly to an enhancement of NE release and not to reuptake inhibition [1]. This contention is based essentially on the observation that NE reuptake blockers leave unaltered the firing rate of 5-HT neurons. The gradual recovery of NE in the presence of the sustained increase in 5-HT neuronal firing may be explained in part the delayed onset of action of bupropion in major depression. References [1] Dong J, Blier P, 2001, Modification of norepinephrine and serotonin, but not dopamine, neuron firing by sustained bupropion treatment. Psychopharmacol 155, 52−57.
P.2.d.017 Behavioral and molecular effects of repeated treatment with citalopram alone or combined with memantine in rats A. Tamburella ° , V. Micale, M. Zammataro, F. Drago. University of Catania, Dept. of Experimental and Clinical Pharmacology, Catania, Italy Hippocampus is considered as a target for antidepressant drugs, since it is one of the major brain areas involved in emotional processes and in the pathogenesis of depression. Preclinical studies show a decreased expression in this area of the nuclear transcription factor cAMP response element binding protein (CREB), considered as a typical sign of impaired neural plasticity in depression, influenced by drugs affecting brain monoamine systems. Thus, the therapeutic effect of several classes of antidepressants is related to a regulation of hippocampal levels of adenylyl cyclase and to the over-expression of this protein (Thome et al., 2000), leading to improved behavioral performance in animal models of depression (Chen et al., 2001). Selective serotonin (5-HT) reuptake inhibitors (SSRIs) have long gained extensive clinical use and are drugs of choice for the treatment of depression. Recently, the glutamatergic system has benn involved in depression. In particular, NMDA receptor antagonists such as the uncompetitive antagonist, memantine (MEM) have been shown to exert antidepressive-like effects in animal models (Rogoz et al., 2002).
S371
The aim of the present study was to evaluate the association of MEM to the SSRI, citalopram on the antidepressive-like effects of the latter in the forced swimming test (FST) and in the expression of CREB protein in hippocampus of rats as assessed by Western Blot analysis. Male Wistar rats were treated i.p. for 14 days with citalopram (8 and 16 mg/kg/day), MEM (2.5 mg/kg) or vehicle. Citalopram 8 mg/kg did not modify the immobility time of rats compared to vehicle. Only at the dose of 16 mg/kg, citalopram treated rats exhibited a better behavioral performance in FST than vehicletreated controls. MEM did not show any change in the reduction of the immobility time when administered alone. When coinjected to citalopram 8 or 16 mg/kg, MEM 2.5 mg/kg improved the behavioral performance of rats in FST (P < 0.05; P < 0.01). Western blot analysis of hippocampal homogenates showed that CREB protein expression is significantly higher in rats treated with citalopram at the dose of 16 mg/kg/day (P < 0.01), but not at the dose of 8 mg/kg/day, in comparison to vehicle-injected controls. Memantine-treated rats also failed to show any change in the hippocampal CREB expression. However, MEM co-administered with both doses of citalopram, induced an increased CREB protein expression as compared to vehicle (P < 0.05; P < 0.01). These findings demonstrate that inefficacious doses of citalopram and MEM, given in combination, are effective in exerting antidepressive effects, improving performances of rats tested in in FST. The combination also induced a CREB protein overexpression, that is recognized as a typical effect of antidepressants, suggesting that co-administration of MEM and citalopram may be useful to improve behavior and to enhance neural plasticity that usually follows chronic antidepressant treatment in rats hippocampus. References [1] Chen ACH, Shirayama Y, Shin KH, Neve RL, Duman RS, 2001, Expression of cAMP element binding protein (CREB) in hippocampus produces an antidepressant effect. Biol Psychiatry 49, 753–762. [2] Thome J, Sakai N, Shin K-H, Steffen C, Zang Y-J, Impey S, Storm D, Duman RS, 2000, cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment. J Neurosci 20, 4030–4036. [3] Rog´oz Z, Skuza G, Maj J, Danysz W, 2002, Synergistic effect of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rats. Neuropharmacology 42, 1024– 1030.
P.2.d.018 Effects from vagus nerve stimulation on rat hippocampal progenitor proliferation D. Revesz ° , M. Tjernstr¨om, E. Ben-Menachem, T. Thorlin. Institute of Clinical Neuroscience, Neurology, G¨oteborg, Sweden Purpose of the study: The birth of new neurons from neuronal stem cells, the process called neurogenesis, has been seen in adult brains from both rodents and humans. The process is especially prominent in the hippocampus, which is involved in mood and memory functions and epilepsy. A new hypothesis for the development of depression in humans has been formed over the last few years, which includes neurogenesis as a factor of importance in the depressive disease: Reduction of neurogenesis in the hippocampus is a causality factor in the generation of depression and stimulated neurogenesis is part of the recovery process from the depressive state (Jacobs et al., 2000). VNS therapy, which has been used successfully for many years in the treatment of epilepsy (BenMenachem, 2002), was early on in its development noted to