- Email: [email protected]
P.1.058 Hyperforin induces release of dopamine and serotonin from rat brain slices
PI, Affectioe di~ov&rs and ant~cle.pre~sa~t~
$198
equilibrium dissociation constant (Kd) of 3.4 nM and a t;max of 919 fmol/mg protein. The uptake of [3H]5-t-IT by human lymphocytes was concentration-dependent, with characteristics of saturable kinetics. Lineweaver-t)urk anal~is yielded a km of 370 nM and V ~ of 2059 fmol/min/105 cells. Immunoblot analysis showed a single band of approximately 70 kDa for rat brain striatum as well as for human lymphocytes and lymphoblasts. A significant decrease in [3H]citalopram binding is observed upon incubation of lymphocytes for 24 or 48 hours in the presence of 10-r M tricydic antidepressants or SSRIs. A profound increase in [3H]citalopram binding is detected upon incubation for the same periods of time in the presence of 10-~ and 10.5 M of the same drugs. C o n e l ~ i o m This study demonstrates that human lyrnphocytes possess a high affinity transport system for 5-HT, with general characteristics and pharmaooldnetic properties which are similar to those of the 5-I-ITT in neuronal tissues and in blood platelets. The expression of the 5-HTT in human peripheral blood lyrrphooytes is modulated upon exposure to different concentration of various antidepressant drugs. These findings might help understand the regulatory action and different efficacies of antidepressant drugs.
References [1] Barkan T, Gurwitz D., Levy O., Weizman A., Rehavi M. Bioohemieal and pharmacological characterizationof the serotonin transporterin human peripheralblood lymphoeytes, European Neuropsyohopharmaoology, In Press
•
[3t-1]monoamines from the tissue to the medium was determined by measurement of radioactivity. Restflts: Exposure of preloaded brain slices to hyperforin induced small though dose dependent release (2 * 10-hM - 2" 10-CM) of both [3I-I]dopamine and [31-I]serotonin. Depolarization with 25mlv2 KC1 (for dopamine) and 50ram (for serotonin) induced dramatic release of the preloaded monoamines. The K + stimulated release of the monoamines was dose dependently attenuated by 15 rain preincubation with hyperforin. The reduction in K + stimulated release of the [3t-I]monoamines correlated with the duration of the preincubation with hypefforin; longer exposure periods yielded lower values of K + evoked release of the monoamines. Incubation of the brain slices with reserpine before the 'qoading" with radiolabeled monoamines was associated with a dose dependent blunting of release due to hyperforin. Amphetamine induced release of [3t-1]dopamine and fenfiuramine induced release of [3I-I]serotonin was higher (23% and 32% respectively) after exposure of the brain slices to hyperforin (4" 10-~M). The increased amphetamine and fenfluramine induced release of the [3t-1]monoamines correlated with the incubation time with hyperforin. Coilel~ioxlS: The data presented in this report support the assumption that hyperforin collapses the transvesiclular pH gradient inducing a redistribution of the monoamines from the vesicular to the cytoplasmic pool. The increased brain levels of dopamine and serotonin following hyperforin or St. John's weft extract administration may be the consequence of their cytoplasmic accumulation.
• HyperforJn induces release of dopamine and serotonin from rat brain slices
IVi. lkehavi, N, Roz, 7"el-Aoio Unioersi~ gackler Facu#y of
Medicine, Dhyxiology and Pharmacolo~, Tel-Aoio, Israel t-lyperforin, found in t-lypericum perforatum (St, John's wort) extracts has antidepressant properties, I-lyperforin has a unique pharmacological profile and it inhibits uptake ofbiogenic monoamines as wall as amino acid transmitters. We have recently showed that the monoamines uptake inhibition exerted by hyperforin is related to its ability to dissipate the pK gradient across the synaptic vesicle membrane thereby interfering with vesicular monoamines storage. In this study we demonstrate that hyperforin induces dose dependent release of preloaded [~H]5I-IT and [3I-I]DA from rat brain slices. We show that hyperforin attenuates depolarization dependent release of monoamines, while increasing monoamine release by amphetamine or fenfiuramine. We demonstrate that preincubation of brain slices with reserpine is associated with dose dependent blunting of release due to hyperforin. Our data indicate that hyperforin induced release of [3H]5HT and [3H]DA refieot elevated cytoplasmic concentration of the two monoamines secondary to the depletion of the synaptic vesicle content and the compartmental redistribution of nerve ending monoamines. [3I-I]monoamines release: Rat brain cortical slices were incubated with 5"10-8M [3I-I]dopamine or [3I-I]serotonin in the presence of 10~Ivi paegyline for 30 rain. The washed slices were placed in baskets with a mesh bottom. Each basket was transferred at 1 rain intervals through a series of vials containing buffer until stabilization of basal [3I-I]monoamine release. For stimulated release, the baskets were transferred to vials containing different stimulators (25mM or 50mM KC1 for 1 rain, 10btM amphetamine for 5 min, 10~M fenfluramine for 5 rain). The rate of release of
Subacute effects of sertraline on attentional and executive functions in major depression
E,L, Constant j , S, Adam 2, B, Qillain j , X, Geron 3, R, Bruyer 3, A, Seghers 1, 1Unioerxit~ Catholique de Youoain, P~yohiatry,
Bru;celle4 Belgium; 2 University of Li@e, NeuropsyeAology Unit, Li@e, Bel~um; 3 Unioersit~ Catholique de Louoain, Cognitioe Neurosoienee Unit, Louoain-la-Neuoe, Belgium
P~-'pose: Several cognitive dysfunctions in depression have been documented in the literatur% concerning attention,executive functions or memory, Several authors have demonstrated difficulties of inhibition during czecutiv¢ tasks, with material of negative emotional valence, I-Iowever~ divergences concerning the severity and reuersibility of cognitive disturbances exist in the literature due to methodological bias (sensitivity of the tests, age of the patients, heterogeneity of the depressive pathologies), l~Ielheds: By using a precise methodology, this study examines attention and caecutive functions in 20 relatively young depressed patients (mean age, 4"],65 yr), presenting a first or second episode of major unipolar depression, all given the same psychopharmacological treatment (sertraline 50 to 75 my/day) in order to investigate the changes in potential attentional and executive loss during a subacute period of treatment of 7 weeks, We compared their performance with that of a group of 26 control suNeots matched %r age and sociocultural level, The cognitive battery (phasic alertness task, classic Stroop test,supraliminal and subliminal emotional Stroop test) took place the firsttime before antidepressant treatment, the second one 3 weeks later and finally the third one W weeks after the first one, Affeetive symptoms were assessed with the self-rated Beck Depression Inventory (BDI) and anxiety syrnptome with the STAI state/traitscale, For statistical analysis, 2 way ANOVAs (Beck Depression Inventory, STAI), 3 way AN©VAs (phasic alertness, classic Stroop, supra-
$198
equilibrium dissociation constant (Kd) of 3.4 nM and a t;max of 919 fmol/mg protein. The uptake of [3H]5-t-IT by human lymphocytes was concentration-dependent, with characteristics of saturable kinetics. Lineweaver-t)urk anal~is yielded a km of 370 nM and V ~ of 2059 fmol/min/105 cells. Immunoblot analysis showed a single band of approximately 70 kDa for rat brain striatum as well as for human lymphocytes and lymphoblasts. A significant decrease in [3H]citalopram binding is observed upon incubation of lymphocytes for 24 or 48 hours in the presence of 10-r M tricydic antidepressants or SSRIs. A profound increase in [3H]citalopram binding is detected upon incubation for the same periods of time in the presence of 10-~ and 10.5 M of the same drugs. C o n e l ~ i o m This study demonstrates that human lyrnphocytes possess a high affinity transport system for 5-HT, with general characteristics and pharmaooldnetic properties which are similar to those of the 5-I-ITT in neuronal tissues and in blood platelets. The expression of the 5-HTT in human peripheral blood lyrrphooytes is modulated upon exposure to different concentration of various antidepressant drugs. These findings might help understand the regulatory action and different efficacies of antidepressant drugs.
References [1] Barkan T, Gurwitz D., Levy O., Weizman A., Rehavi M. Bioohemieal and pharmacological characterizationof the serotonin transporterin human peripheralblood lymphoeytes, European Neuropsyohopharmaoology, In Press
•
[3t-1]monoamines from the tissue to the medium was determined by measurement of radioactivity. Restflts: Exposure of preloaded brain slices to hyperforin induced small though dose dependent release (2 * 10-hM - 2" 10-CM) of both [3I-I]dopamine and [31-I]serotonin. Depolarization with 25mlv2 KC1 (for dopamine) and 50ram (for serotonin) induced dramatic release of the preloaded monoamines. The K + stimulated release of the monoamines was dose dependently attenuated by 15 rain preincubation with hyperforin. The reduction in K + stimulated release of the [3t-I]monoamines correlated with the duration of the preincubation with hypefforin; longer exposure periods yielded lower values of K + evoked release of the monoamines. Incubation of the brain slices with reserpine before the 'qoading" with radiolabeled monoamines was associated with a dose dependent blunting of release due to hyperforin. Amphetamine induced release of [3t-1]dopamine and fenfiuramine induced release of [3I-I]serotonin was higher (23% and 32% respectively) after exposure of the brain slices to hyperforin (4" 10-~M). The increased amphetamine and fenfluramine induced release of the [3t-1]monoamines correlated with the incubation time with hyperforin. Coilel~ioxlS: The data presented in this report support the assumption that hyperforin collapses the transvesiclular pH gradient inducing a redistribution of the monoamines from the vesicular to the cytoplasmic pool. The increased brain levels of dopamine and serotonin following hyperforin or St. John's weft extract administration may be the consequence of their cytoplasmic accumulation.
• HyperforJn induces release of dopamine and serotonin from rat brain slices
IVi. lkehavi, N, Roz, 7"el-Aoio Unioersi~ gackler Facu#y of
Medicine, Dhyxiology and Pharmacolo~, Tel-Aoio, Israel t-lyperforin, found in t-lypericum perforatum (St, John's wort) extracts has antidepressant properties, I-lyperforin has a unique pharmacological profile and it inhibits uptake ofbiogenic monoamines as wall as amino acid transmitters. We have recently showed that the monoamines uptake inhibition exerted by hyperforin is related to its ability to dissipate the pK gradient across the synaptic vesicle membrane thereby interfering with vesicular monoamines storage. In this study we demonstrate that hyperforin induces dose dependent release of preloaded [~H]5I-IT and [3I-I]DA from rat brain slices. We show that hyperforin attenuates depolarization dependent release of monoamines, while increasing monoamine release by amphetamine or fenfiuramine. We demonstrate that preincubation of brain slices with reserpine is associated with dose dependent blunting of release due to hyperforin. Our data indicate that hyperforin induced release of [3H]5HT and [3H]DA refieot elevated cytoplasmic concentration of the two monoamines secondary to the depletion of the synaptic vesicle content and the compartmental redistribution of nerve ending monoamines. [3I-I]monoamines release: Rat brain cortical slices were incubated with 5"10-8M [3I-I]dopamine or [3I-I]serotonin in the presence of 10~Ivi paegyline for 30 rain. The washed slices were placed in baskets with a mesh bottom. Each basket was transferred at 1 rain intervals through a series of vials containing buffer until stabilization of basal [3I-I]monoamine release. For stimulated release, the baskets were transferred to vials containing different stimulators (25mM or 50mM KC1 for 1 rain, 10btM amphetamine for 5 min, 10~M fenfluramine for 5 rain). The rate of release of
Subacute effects of sertraline on attentional and executive functions in major depression
E,L, Constant j , S, Adam 2, B, Qillain j , X, Geron 3, R, Bruyer 3, A, Seghers 1, 1Unioerxit~ Catholique de Youoain, P~yohiatry,
Bru;celle4 Belgium; 2 University of Li@e, NeuropsyeAology Unit, Li@e, Bel~um; 3 Unioersit~ Catholique de Louoain, Cognitioe Neurosoienee Unit, Louoain-la-Neuoe, Belgium
P~-'pose: Several cognitive dysfunctions in depression have been documented in the literatur% concerning attention,executive functions or memory, Several authors have demonstrated difficulties of inhibition during czecutiv¢ tasks, with material of negative emotional valence, I-Iowever~ divergences concerning the severity and reuersibility of cognitive disturbances exist in the literature due to methodological bias (sensitivity of the tests, age of the patients, heterogeneity of the depressive pathologies), l~Ielheds: By using a precise methodology, this study examines attention and caecutive functions in 20 relatively young depressed patients (mean age, 4"],65 yr), presenting a first or second episode of major unipolar depression, all given the same psychopharmacological treatment (sertraline 50 to 75 my/day) in order to investigate the changes in potential attentional and executive loss during a subacute period of treatment of 7 weeks, We compared their performance with that of a group of 26 control suNeots matched %r age and sociocultural level, The cognitive battery (phasic alertness task, classic Stroop test,supraliminal and subliminal emotional Stroop test) took place the firsttime before antidepressant treatment, the second one 3 weeks later and finally the third one W weeks after the first one, Affeetive symptoms were assessed with the self-rated Beck Depression Inventory (BDI) and anxiety syrnptome with the STAI state/traitscale, For statistical analysis, 2 way ANOVAs (Beck Depression Inventory, STAI), 3 way AN©VAs (phasic alertness, classic Stroop, supra-