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125. Glutamatergic modulation of motor and limbic dopaminergic circuits
38S
BIOLPSYCHIATRY 1998;43:1S-133S
growingbodyof evidencesuggeststhat monotropic glutamatereceptor expression and regulation may be abnormalin schizophrenics.Similarly, the serotonin receptor subtypes, particularly those that are 5-HT2.-like,appear to be impotiant in schizophreniabased on their pharmacologicalproperties (agonismof which producespsychotomimetic effects and significant affinities for atypical antipsychotics). Recent studies have shownthat glutamatereceptor modtdationalters serotonin release in the striatum and hippocampus.Less is known aboutthe compensatorychangesin serotoninreceptorexpressionafter glutamate receptor modulator treatment. In order to address this question, Sprague-Dawleyrats were treated daily with the AMPA and/or kainate modulators CNQX, NBQX, GYKI 52466, rikrzole, aniracetam,or vehicle for one week, and 5-HT2.,5-HTZC, 5-HT6,and 5-HT7mRNA levels were measured in hippoeampus,striatum, and cortex by in situ hybridization.The results indicate that AMPAand kainate antagonists caused an increase in 5-HT2amRNA levels in hippocampusand cortex, and a decrease in 5-HT6mRNA levels in nucleus accumbens and dorsal stnatum, suggesting that these subtypes are more sensitive to modulationby glutamatergiccompounds. This demonstrationof regulationof serotoninreceptor expressionby glutamate receptor modulation provides further evidence for the interaction of these two neurotransmitter systems at the level of receptor expression, and suggests a possible mechanism by which dysregulationof one of these transmitter systems may impingeupon the other as part of the pathophysiologyof schizophrenia.
125. GLUTAMATERGIC MODULATION OF MOTOR AND LIMBIC DOPAMINERGIC CIRCUITS D.J. Healy & J.H. Meador-Woodruff
Thursday Abstracts
126. MELATONIN, MAO-A INHIBITOR, BEFLOXATONE, AND RAT STRAINGENDER EFFECTS P.J. Requintinal’2, V. Rovei3 & G.F. Oxenkrugl ‘Departmentof Psychiatryand PinealResearehLaboratory,St. Elizabeth’sMedicalCenterof BostonlMts University,Boston,MA, 02135;‘providenceVA MedicalCenter,Providence,R.I. and %yn~ Research,Departmentof PreclinicalResearch,Bagneux, France(VR) Sincethe first observationof the stimulationof the rat pinealmelatonin biosynthesisby the selective MAO-A (but not MAO-B) inhibitors (Oxenkruget al.,1984),inhibitionof MAO-Awas reportedto increase monkeysspinalfluidsmelatoninlevels(Garricket al., 1987)andhuman bloodmelatoninandurine6-hydroxymelatonin levels(Biecketal., 1988; Goldenet al., 1988;Murphyet sL, 1986;Oxenkruget aL,1986)(for review see Oxenkrug,1991).The present study aimed to evaluatethe effectof a newreversible,highlypotent,selectiveMAO-Ainhibitorwith antidepressantactivity,Mloxatone, on thepinealmelatoninbiosynthesis in rats of different strains and gender. Pined N-acetyl serotonin, melatonin,serotoninand 5-hydroxyindoleacetic acid (5-HL4A)levelsof Spraque-Dawleyand Fisher 344Nrats were determinedby the HPLCfluorimetricprocedure.Acutebefloxatoneadministration(s.c.) resulted in a dose-dependentincreaseof pineallevels of N-acetylsemtoninand melatoninand decreaseof 5-HIAAcontentin both strains of rats. The befloxatoneeffect in Fischer rats was hotieeableat the dose of 0.05 mfig while the minimal dose of hefloxatonethat stimulatedpined melatoninbiosynthesisin Sprague-Dawleyratswas0.5 mglkg.Malerats were significantlymore sensitiveto befloxatoneeffect than femalerats. Melatoninergiceffects of the selective MAO-A inhibitorshave been suggestedto mediatetheirclinicalantidepressiveaction(Oxenkruget rd., 1986).The deseribedgender-straindifferencesin hefloxatone-indueed stimulationof melatoninbiosynthesismighthe usefulfor the understanding of the clinicrdefficacyof the selective,reversibleMAO-Ainhibitor, befloxatone.
MentalHealthResearchInstituteand Departmentof Psychiatry, Universityof Michigan,AnnArborMI Dopamine is the neurotransmitter most often implicated in the pathogenesis of schizophrenia. However, glutamate has also been implicated,particularly the NMDAsubtypeof glutamatereceptor, as NMDA receptor antagonists like phencyclidineare psychomimetic, while positive modulatorsof the NMDAreceptor amelioratenegative psychoticsymptoms.These findingshave led investigatorsto attempt to synthesizethese data, resulting in a model of dopumine-glntarnate interactions in limbic cortex and striatum as a potential substrate for symptom production in schizophrenia. There are several corticalsubcorticalcircuits that appear to subservelimbic or motor (extrapyramidal) functions, and each contains dopaminergicprojections that appearto be modulatedby glutamatergicinput.We performeda series of experimentsto examinethe relationshipbetweenglutamatereceptor subtype and dopaminergiccircuit to begin to explore differences in the anatomical substrate of limbic and motor function. One set of rats was treated with the NMDA receptor antagonist MK-801 and dopaminereceptor expressionwas measuredin cortex, striatum, and midbrain.A separate set of animals was treated with AMPA/kainatc receptor modulatorsand dopaminereceptor expressionwas measured in the same regions. The results indicate that NMDA receptor antagonistsseem to preferentiallyaffect limbic dopaminergicregions over mntor regions, while AMPA/kainatereceptor modulatorsdifferentially affect the direet and indirect striatal (motor) outflow pathways. These results may suggestthat treatmentstargeting the NMDA receptor may improve psychotic symptomswithout affecting extrapyramidal symptoms,while treatment with AMPAreceptor modulators may affect extrapyramidalsymptoms.
127. ENTORHINAL CORTICAL PREPROSOMATOSTATIN mRNA in PSYCHIATRIC DISORDERS S.E. Bachus, T.M. Hyde, S.L. Rubinstein, M.M. Herman & J.E. Kleinman ClinicrdBrainDisordersBranch,IWMHNeuroscienceCenterat St. Elizabeth, Washington,D.C., 20032 Somatostatin-likeimmunoreactivityhas been foundto he decreasedin CSFfromschizophrenicsanddepressedpatients(l). We haveexamined mRNA for preprosomatostatin(ppSS) at postmortem from patient populationsin the intermediatesubarea of entorhinalcortex (ERC),a region where we have found decreases in mRNAs for other pe.ptide neuromodulators,such as cholccystokininand thyrotrophinreleasing hormone(2), to ascertainwhethera somatostatinabnormalitymightbe confirmed in the brain. Fresh-frozensections (14 p -thick) of the intermediatesubareaof ERCfromnormalcontrols(n= 12),schizophrenics (n= 10),suicides(n=7) and neumleptic-treatedpatientswithbipolar affective disorder (n=4) were labelled by in situ hybridizationhistoche~sq wi~ ~ sss.la~ll~ oligonucleotideprobe for PPSS-A. TheprogramNIHIMAGE(Rasbartd,NIH)wasusedto quantifythe label in superficialanddeeplayersof ERC.Statisticswereby 2 wayANOVA for diagnosis (between groups) and layer (within subjects) effeets,
BIOLPSYCHIATRY 1998;43:1S-133S
growingbodyof evidencesuggeststhat monotropic glutamatereceptor expression and regulation may be abnormalin schizophrenics.Similarly, the serotonin receptor subtypes, particularly those that are 5-HT2.-like,appear to be impotiant in schizophreniabased on their pharmacologicalproperties (agonismof which producespsychotomimetic effects and significant affinities for atypical antipsychotics). Recent studies have shownthat glutamatereceptor modtdationalters serotonin release in the striatum and hippocampus.Less is known aboutthe compensatorychangesin serotoninreceptorexpressionafter glutamate receptor modulator treatment. In order to address this question, Sprague-Dawleyrats were treated daily with the AMPA and/or kainate modulators CNQX, NBQX, GYKI 52466, rikrzole, aniracetam,or vehicle for one week, and 5-HT2.,5-HTZC, 5-HT6,and 5-HT7mRNA levels were measured in hippoeampus,striatum, and cortex by in situ hybridization.The results indicate that AMPAand kainate antagonists caused an increase in 5-HT2amRNA levels in hippocampusand cortex, and a decrease in 5-HT6mRNA levels in nucleus accumbens and dorsal stnatum, suggesting that these subtypes are more sensitive to modulationby glutamatergiccompounds. This demonstrationof regulationof serotoninreceptor expressionby glutamate receptor modulation provides further evidence for the interaction of these two neurotransmitter systems at the level of receptor expression, and suggests a possible mechanism by which dysregulationof one of these transmitter systems may impingeupon the other as part of the pathophysiologyof schizophrenia.
125. GLUTAMATERGIC MODULATION OF MOTOR AND LIMBIC DOPAMINERGIC CIRCUITS D.J. Healy & J.H. Meador-Woodruff
Thursday Abstracts
126. MELATONIN, MAO-A INHIBITOR, BEFLOXATONE, AND RAT STRAINGENDER EFFECTS P.J. Requintinal’2, V. Rovei3 & G.F. Oxenkrugl ‘Departmentof Psychiatryand PinealResearehLaboratory,St. Elizabeth’sMedicalCenterof BostonlMts University,Boston,MA, 02135;‘providenceVA MedicalCenter,Providence,R.I. and %yn~ Research,Departmentof PreclinicalResearch,Bagneux, France(VR) Sincethe first observationof the stimulationof the rat pinealmelatonin biosynthesisby the selective MAO-A (but not MAO-B) inhibitors (Oxenkruget al.,1984),inhibitionof MAO-Awas reportedto increase monkeysspinalfluidsmelatoninlevels(Garricket al., 1987)andhuman bloodmelatoninandurine6-hydroxymelatonin levels(Biecketal., 1988; Goldenet al., 1988;Murphyet sL, 1986;Oxenkruget aL,1986)(for review see Oxenkrug,1991).The present study aimed to evaluatethe effectof a newreversible,highlypotent,selectiveMAO-Ainhibitorwith antidepressantactivity,Mloxatone, on thepinealmelatoninbiosynthesis in rats of different strains and gender. Pined N-acetyl serotonin, melatonin,serotoninand 5-hydroxyindoleacetic acid (5-HL4A)levelsof Spraque-Dawleyand Fisher 344Nrats were determinedby the HPLCfluorimetricprocedure.Acutebefloxatoneadministration(s.c.) resulted in a dose-dependentincreaseof pineallevels of N-acetylsemtoninand melatoninand decreaseof 5-HIAAcontentin both strains of rats. The befloxatoneeffect in Fischer rats was hotieeableat the dose of 0.05 mfig while the minimal dose of hefloxatonethat stimulatedpined melatoninbiosynthesisin Sprague-Dawleyratswas0.5 mglkg.Malerats were significantlymore sensitiveto befloxatoneeffect than femalerats. Melatoninergiceffects of the selective MAO-A inhibitorshave been suggestedto mediatetheirclinicalantidepressiveaction(Oxenkruget rd., 1986).The deseribedgender-straindifferencesin hefloxatone-indueed stimulationof melatoninbiosynthesismighthe usefulfor the understanding of the clinicrdefficacyof the selective,reversibleMAO-Ainhibitor, befloxatone.
MentalHealthResearchInstituteand Departmentof Psychiatry, Universityof Michigan,AnnArborMI Dopamine is the neurotransmitter most often implicated in the pathogenesis of schizophrenia. However, glutamate has also been implicated,particularly the NMDAsubtypeof glutamatereceptor, as NMDA receptor antagonists like phencyclidineare psychomimetic, while positive modulatorsof the NMDAreceptor amelioratenegative psychoticsymptoms.These findingshave led investigatorsto attempt to synthesizethese data, resulting in a model of dopumine-glntarnate interactions in limbic cortex and striatum as a potential substrate for symptom production in schizophrenia. There are several corticalsubcorticalcircuits that appear to subservelimbic or motor (extrapyramidal) functions, and each contains dopaminergicprojections that appearto be modulatedby glutamatergicinput.We performeda series of experimentsto examinethe relationshipbetweenglutamatereceptor subtype and dopaminergiccircuit to begin to explore differences in the anatomical substrate of limbic and motor function. One set of rats was treated with the NMDA receptor antagonist MK-801 and dopaminereceptor expressionwas measuredin cortex, striatum, and midbrain.A separate set of animals was treated with AMPA/kainatc receptor modulatorsand dopaminereceptor expressionwas measured in the same regions. The results indicate that NMDA receptor antagonistsseem to preferentiallyaffect limbic dopaminergicregions over mntor regions, while AMPA/kainatereceptor modulatorsdifferentially affect the direet and indirect striatal (motor) outflow pathways. These results may suggestthat treatmentstargeting the NMDA receptor may improve psychotic symptomswithout affecting extrapyramidal symptoms,while treatment with AMPAreceptor modulators may affect extrapyramidalsymptoms.
127. ENTORHINAL CORTICAL PREPROSOMATOSTATIN mRNA in PSYCHIATRIC DISORDERS S.E. Bachus, T.M. Hyde, S.L. Rubinstein, M.M. Herman & J.E. Kleinman ClinicrdBrainDisordersBranch,IWMHNeuroscienceCenterat St. Elizabeth, Washington,D.C., 20032 Somatostatin-likeimmunoreactivityhas been foundto he decreasedin CSFfromschizophrenicsanddepressedpatients(l). We haveexamined mRNA for preprosomatostatin(ppSS) at postmortem from patient populationsin the intermediatesubarea of entorhinalcortex (ERC),a region where we have found decreases in mRNAs for other pe.ptide neuromodulators,such as cholccystokininand thyrotrophinreleasing hormone(2), to ascertainwhethera somatostatinabnormalitymightbe confirmed in the brain. Fresh-frozensections (14 p -thick) of the intermediatesubareaof ERCfromnormalcontrols(n= 12),schizophrenics (n= 10),suicides(n=7) and neumleptic-treatedpatientswithbipolar affective disorder (n=4) were labelled by in situ hybridizationhistoche~sq wi~ ~ sss.la~ll~ oligonucleotideprobe for PPSS-A. TheprogramNIHIMAGE(Rasbartd,NIH)wasusedto quantifythe label in superficialanddeeplayersof ERC.Statisticswereby 2 wayANOVA for diagnosis (between groups) and layer (within subjects) effeets,