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The effects of selective monoamine oxidases A or B inhibitors on the anxiogenic-like behaviour in mice
Poster session I
BIOL. PSYCHIATRY 1997:42:15-2975
of zlprasidone in young healthy volunteers. In vitro studies using human microsomes have shown that CYP 3A4 Is responsible for the formation major of the metabolites of ziprasldone. Subjects (n = 10) were randomized to ziprasidone 40 mg alone, zlprasidone 40 mg plus Maalox41 30 ml (Maalox41 was also given at becltime the evening before ziprasidone and 20 min after the midday and evening meals on the day of ziprasidone dosing), and ziprasidone 40 mg plus cimetldine 800 mg (cimetidine was also given for 2 days before and 1 day after ziprasidone dosing). On each ziprasidone dosing day (separated by 7 days), blood samples were collected immediately prior to and up to 36 h following ziprasidone for analysis of serum ziprasidone levels and calculation of pharmacoklnetic variables. While Maalox41 delayed the occurrence of Cmax by 3 h, there were no statistically significant differences In Cmu, AU~, or Ket between the ziprasidone + Maalox<8 and the ziprasidone groups. When ziprasidone was administered with clmetidine, there were no statistically significant changes in AU~, or Cmu, Tmax or Ket compared with zlprasldone aione. The lack of clinically significant interaction between ziprasldone and clmetidine indicates that the metabolism of ziprasidone Is not affected by the CYP 3A4 inhibitor. cimetidine, presumably because altemative metabolic pathways were utilized. These results indicate that Inhibitors of CYP 3A4 and Maalox41 are unlikely to alter the pharmacokinetics of ziprasidone.
114-1191
Determination of methylcobalamln In serum by IIquld-chromatography-mass spectrometry with selected-Ion monitoring
I Transmitter dysfunction and neural plasticity responses In schizophrenia
B.Y. Glenthl!Jj, R.P. Hemmingsen. Department of Psychiatry E, University Hospital Bispebjerg, DK-24oo Copenhagen, Denmark The authors have previously demonstrated, that It Is possible to modify mesolimblc dopaminergic activity by Intermittent electrical stimulations (IES) of the cells in the ventral tegmental area (VTA). Stimulated rats demon• strated a significantly potentiated response to both electrical stimulations and challenge with dopamine (DA) agonists. Between stimulation periods sensitized rats demonstrated changes In social behaviours. The behavioural response to stimulation was suppressed by both by DA 01 and 02 antag• onists. In an unpublished study a shorter-lasting stimulation regimen was used. Sensitization of behaviours related to the mesolimbic dopaminergic system was comparable to what was observed In previous experiments. However, using the faster sensitization regimen, only rats that were both sensitized by IES and lesioned in prefrontal cortex 3 weeks old by subpial aspiration demonstrated behavioural changes between stimulations. Based on our own and others preclinical and clinical studies we have proposed a hypothesis that can explain how a cortical glutamaterglc dysfunction I can dispose to spontaneous sensitization of the mesolimbic dopaminergic sys· tem and progressive evolution of psychosis. A further developed hypothesis focusing on the consequence of transmitted dysfunction for perception and for the ability of the individual to adapt to a constantly changing environment will be presented.
114-1221
M. Nomura. Y. Sakamoto, N. Nagashlma, N. Takehara, K. Kitamura. Saitama Medical School, Department of Physiology. Saltama. Japan To know about a correlation between repeated methylcobalamin treatment for agrypnotic rhythms and its curative effect. the following method was developed. Methods: Uquid chromatography-mass spectrometry (LC-MS) with se• lected-Ion monitoring (SIM) was used to analyze the quantity of methyl• cobalamin in serum. Four kinds of vitamin B12-hydroxo, cyano, adenosyl (DBCC), and methylcobalamin were completely separated using HPLC with a capillary ODS column. A linear methanol gradient was used for the elution and the eluate was directly leaded to ion source of MS and the fast atomic bombardment (FAB) mode was used for ionization. Each type of Vitamin B12 showed high intensity mlz 1329. which Is daughter ion. Therefore, the mlz 1329 was monitored to detect the presence of each B12 vitamin. A synthetic peptide was used as the internal standard. Sera that was added 4 volumes of acetate buffer and boiled and then centrifuged. A supernatant was subjected to a pretreatment column to remove salts and concentrate. The absorbed substance was then eluted with 7O'Yo methanol and dried up as a sample for SIM analysis. Results: The method was rapid, selective. and reliable to analyze changes In methylcobalamln concentration In the serum after repeated administration.
114-120
114-121
I The assessment of hypothalamlc-pltultary-adrenal (HPA) axis by dexamethasone suppression test In patients with major depression with positive or negative allergic tests results
438
Effects of serotonin 1a receptor agonist, fleslnoxan, on the locomotor activity of rats
M. Niwa, M. Kubota, M. Atobe, K. Kobayashi, A. Suwabe, M. Nakagawara, S. Kanba. Department of Neuropsychiatry. Yamanashl Medical University, Yamanashl, Japan We have reported that serotonin 1A receptor agonist, Ipsapirone, Increased locomotor activity In rats. However, ipsapirone Is metabolized to form 1·(2-pyrimidinyl)-piperazine (l-PP) which acts as an a-2 adrenoceptor antag• onist. It Is well known that a-2 adrenoceptor antagonists increase locomotor activity In rats. Flesinoxan, another compound of serotonin 1A receptor ag• onist, is not metabolized to form 1-PP. In addition, it has been reported that lIesinoxan nor its metabolites Is an a-2 adrenoceptor antagonist. Therefore, in this study we examined if selective stimulation of serotonin 1A receptor can Increase locomotor activity using f1esinoxan. Methods: Flesinoxan (0.5, 5, 10 mglkg,) was Injected Intraperitoneally into rat (eight-week old male Wistar strain) at 10:00 AM. Locomotor activity was counted every thirty minutes with photocell activity recording devices. Results and Conclusion: The injection of liesinoxan (5. 10 mglkg) signif• icantly Increased locomotor activity In rats compared with the saline-injected rats. This result suggests that lIesinoxan-lnduced-increase of locomotor activity In rats Is not mediated by a-2 adrenoceptor.
114-1231
The effects of selective monoamine oxidases A or B Inhibitors on the anxlogenic-Iike behaviour In mice
M. Dabkowska. Department of Psychiatry. Unlv. of Medical Sciences, Bydgoszcz, Poland
L de Angelis. Department of Biomedical Sciences, The School of Medicine. University of Trieste. Trieste, Italy
The allergic reactivity of atopic type was Investigated in patients with mood disorders in the course of depressive episode. The diagnoses were confirmed using DSM IV criteria. Methods: The assessment of the allergic reactivity was done by three methods: 1. Skin Intradermal tests to common 10 allergies (in 27 patients). 2. Serum concentration oflgE (in 37 patients) was estimated by "sandwich" enzyme Immunoassay in vitro using monoclonal antibodies antHgE. The concentration of totallgE was measured by means of spectrophotometric method. 3. The presence of specific antibodies IgE (In 32 patients) for inhaled allergens by means of Phadiatop EIA test (Pharmacia). The activity of HPA axis was assess by Dexamethasone Suppression Test (carrol et al., 1981). Results: A significant correlation was found between serum IgE concen• tration and 24 h post-dexamethasone cortisol concentration (r 0.36, P o041). Conclusions: In patients with depression the abnormally high pro• d~on ofrgE was shown to have some connection with increased activity of HPA axis. This may resemble the associations found with other Indices of Immunological alteration In depression.
The new generation of selective and reversible MAD-A Inhibitors RIMA antidepressants, Inhibit preferentially type A monoamine oxidase enzyme, which in tum selectively decreases serotonin deamlnation, producing a pro-serotoninergic effect. This effect may be Important for the anxiolytic-Iike properties of moclobemide, a RIMA drug. In light of the foregoing information, the purpose of the present study was to assess the putative anxiolytic effects of moclobemide in an experimental model of anxiety: the light/dark aversion test. In mice, these chronic effects were compared with those of selegiline, an Irreversible and selective MAD-B inhibitor. For comparative purpose, the chronic effects of a well-known anxiolylic drug, i.e. lorazepam, were also evaluated. In the present investigation, an anxiogenic-Iike behaviour was Induced by pretreatment 01 subconvulsant doses of pentylentetrazole (15 mglkg i.p.). Results showed that moclobemide, In contrast to selegiline, displayed anxiolytic properties, as well as lorazepam. In summary, these data confirm and extend previous preclinical and clinical studies by providing an Important Indication of the ability of the antidepressant mocIobemlde to antagonize anxiety-related behaviour.
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BIOL. PSYCHIATRY 1997:42:15-2975
of zlprasidone in young healthy volunteers. In vitro studies using human microsomes have shown that CYP 3A4 Is responsible for the formation major of the metabolites of ziprasldone. Subjects (n = 10) were randomized to ziprasidone 40 mg alone, zlprasidone 40 mg plus Maalox41 30 ml (Maalox41 was also given at becltime the evening before ziprasidone and 20 min after the midday and evening meals on the day of ziprasidone dosing), and ziprasidone 40 mg plus cimetldine 800 mg (cimetidine was also given for 2 days before and 1 day after ziprasidone dosing). On each ziprasidone dosing day (separated by 7 days), blood samples were collected immediately prior to and up to 36 h following ziprasidone for analysis of serum ziprasidone levels and calculation of pharmacoklnetic variables. While Maalox41 delayed the occurrence of Cmax by 3 h, there were no statistically significant differences In Cmu, AU~, or Ket between the ziprasidone + Maalox<8 and the ziprasidone groups. When ziprasidone was administered with clmetidine, there were no statistically significant changes in AU~, or Cmu, Tmax or Ket compared with zlprasldone aione. The lack of clinically significant interaction between ziprasldone and clmetidine indicates that the metabolism of ziprasidone Is not affected by the CYP 3A4 inhibitor. cimetidine, presumably because altemative metabolic pathways were utilized. These results indicate that Inhibitors of CYP 3A4 and Maalox41 are unlikely to alter the pharmacokinetics of ziprasidone.
114-1191
Determination of methylcobalamln In serum by IIquld-chromatography-mass spectrometry with selected-Ion monitoring
I Transmitter dysfunction and neural plasticity responses In schizophrenia
B.Y. Glenthl!Jj, R.P. Hemmingsen. Department of Psychiatry E, University Hospital Bispebjerg, DK-24oo Copenhagen, Denmark The authors have previously demonstrated, that It Is possible to modify mesolimblc dopaminergic activity by Intermittent electrical stimulations (IES) of the cells in the ventral tegmental area (VTA). Stimulated rats demon• strated a significantly potentiated response to both electrical stimulations and challenge with dopamine (DA) agonists. Between stimulation periods sensitized rats demonstrated changes In social behaviours. The behavioural response to stimulation was suppressed by both by DA 01 and 02 antag• onists. In an unpublished study a shorter-lasting stimulation regimen was used. Sensitization of behaviours related to the mesolimbic dopaminergic system was comparable to what was observed In previous experiments. However, using the faster sensitization regimen, only rats that were both sensitized by IES and lesioned in prefrontal cortex 3 weeks old by subpial aspiration demonstrated behavioural changes between stimulations. Based on our own and others preclinical and clinical studies we have proposed a hypothesis that can explain how a cortical glutamaterglc dysfunction I can dispose to spontaneous sensitization of the mesolimbic dopaminergic sys· tem and progressive evolution of psychosis. A further developed hypothesis focusing on the consequence of transmitted dysfunction for perception and for the ability of the individual to adapt to a constantly changing environment will be presented.
114-1221
M. Nomura. Y. Sakamoto, N. Nagashlma, N. Takehara, K. Kitamura. Saitama Medical School, Department of Physiology. Saltama. Japan To know about a correlation between repeated methylcobalamin treatment for agrypnotic rhythms and its curative effect. the following method was developed. Methods: Uquid chromatography-mass spectrometry (LC-MS) with se• lected-Ion monitoring (SIM) was used to analyze the quantity of methyl• cobalamin in serum. Four kinds of vitamin B12-hydroxo, cyano, adenosyl (DBCC), and methylcobalamin were completely separated using HPLC with a capillary ODS column. A linear methanol gradient was used for the elution and the eluate was directly leaded to ion source of MS and the fast atomic bombardment (FAB) mode was used for ionization. Each type of Vitamin B12 showed high intensity mlz 1329. which Is daughter ion. Therefore, the mlz 1329 was monitored to detect the presence of each B12 vitamin. A synthetic peptide was used as the internal standard. Sera that was added 4 volumes of acetate buffer and boiled and then centrifuged. A supernatant was subjected to a pretreatment column to remove salts and concentrate. The absorbed substance was then eluted with 7O'Yo methanol and dried up as a sample for SIM analysis. Results: The method was rapid, selective. and reliable to analyze changes In methylcobalamln concentration In the serum after repeated administration.
114-120
114-121
I The assessment of hypothalamlc-pltultary-adrenal (HPA) axis by dexamethasone suppression test In patients with major depression with positive or negative allergic tests results
438
Effects of serotonin 1a receptor agonist, fleslnoxan, on the locomotor activity of rats
M. Niwa, M. Kubota, M. Atobe, K. Kobayashi, A. Suwabe, M. Nakagawara, S. Kanba. Department of Neuropsychiatry. Yamanashl Medical University, Yamanashl, Japan We have reported that serotonin 1A receptor agonist, Ipsapirone, Increased locomotor activity In rats. However, ipsapirone Is metabolized to form 1·(2-pyrimidinyl)-piperazine (l-PP) which acts as an a-2 adrenoceptor antag• onist. It Is well known that a-2 adrenoceptor antagonists increase locomotor activity In rats. Flesinoxan, another compound of serotonin 1A receptor ag• onist, is not metabolized to form 1-PP. In addition, it has been reported that lIesinoxan nor its metabolites Is an a-2 adrenoceptor antagonist. Therefore, in this study we examined if selective stimulation of serotonin 1A receptor can Increase locomotor activity using f1esinoxan. Methods: Flesinoxan (0.5, 5, 10 mglkg,) was Injected Intraperitoneally into rat (eight-week old male Wistar strain) at 10:00 AM. Locomotor activity was counted every thirty minutes with photocell activity recording devices. Results and Conclusion: The injection of liesinoxan (5. 10 mglkg) signif• icantly Increased locomotor activity In rats compared with the saline-injected rats. This result suggests that lIesinoxan-lnduced-increase of locomotor activity In rats Is not mediated by a-2 adrenoceptor.
114-1231
The effects of selective monoamine oxidases A or B Inhibitors on the anxlogenic-Iike behaviour In mice
M. Dabkowska. Department of Psychiatry. Unlv. of Medical Sciences, Bydgoszcz, Poland
L de Angelis. Department of Biomedical Sciences, The School of Medicine. University of Trieste. Trieste, Italy
The allergic reactivity of atopic type was Investigated in patients with mood disorders in the course of depressive episode. The diagnoses were confirmed using DSM IV criteria. Methods: The assessment of the allergic reactivity was done by three methods: 1. Skin Intradermal tests to common 10 allergies (in 27 patients). 2. Serum concentration oflgE (in 37 patients) was estimated by "sandwich" enzyme Immunoassay in vitro using monoclonal antibodies antHgE. The concentration of totallgE was measured by means of spectrophotometric method. 3. The presence of specific antibodies IgE (In 32 patients) for inhaled allergens by means of Phadiatop EIA test (Pharmacia). The activity of HPA axis was assess by Dexamethasone Suppression Test (carrol et al., 1981). Results: A significant correlation was found between serum IgE concen• tration and 24 h post-dexamethasone cortisol concentration (r 0.36, P o041). Conclusions: In patients with depression the abnormally high pro• d~on ofrgE was shown to have some connection with increased activity of HPA axis. This may resemble the associations found with other Indices of Immunological alteration In depression.
The new generation of selective and reversible MAD-A Inhibitors RIMA antidepressants, Inhibit preferentially type A monoamine oxidase enzyme, which in tum selectively decreases serotonin deamlnation, producing a pro-serotoninergic effect. This effect may be Important for the anxiolytic-Iike properties of moclobemide, a RIMA drug. In light of the foregoing information, the purpose of the present study was to assess the putative anxiolytic effects of moclobemide in an experimental model of anxiety: the light/dark aversion test. In mice, these chronic effects were compared with those of selegiline, an Irreversible and selective MAD-B inhibitor. For comparative purpose, the chronic effects of a well-known anxiolylic drug, i.e. lorazepam, were also evaluated. In the present investigation, an anxiogenic-Iike behaviour was Induced by pretreatment 01 subconvulsant doses of pentylentetrazole (15 mglkg i.p.). Results showed that moclobemide, In contrast to selegiline, displayed anxiolytic properties, as well as lorazepam. In summary, these data confirm and extend previous preclinical and clinical studies by providing an Important Indication of the ability of the antidepressant mocIobemlde to antagonize anxiety-related behaviour.
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