Subchronic memantine induced concurrent functional disconnectivity and altered ultra-structural tissue integrity in the rodent brain: revealed by multimodal MRI
Background An effective NMDA antagonist imaging model may find key utility in advancing schizophrenia drug discovery research. We investigated effects of subchronic treatment with the NMDA antagonist memantine by using behavioural observation and multimodal MRI. Methods Pharmacological MRI (phMRI) w...
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| Veröffentlicht in: | Psychopharmacology 2013-06, Vol.227 (3), p.479-491 |
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| creator | Sekar, S. Jonckers, E. Verhoye, M. Willems, R. Veraart, J. Van Audekerke, J. Couto, J. Giugliano, M. Wuyts, K. Dedeurwaerdere, S. Sijbers, J. Mackie, C. Ver Donck, L. Steckler, T. Van der Linden, A. |
| description | Background
An effective NMDA antagonist imaging model may find key utility in advancing schizophrenia drug discovery research. We investigated effects of subchronic treatment with the NMDA antagonist memantine by using behavioural observation and multimodal MRI.
Methods
Pharmacological MRI (phMRI) was used to map the neuroanatomical binding sites of memantine after acute and subchronic treatment. Resting state fMRI (rs-fMRI) and diffusion MRI were used to study the changes in functional connectivity (FC) and ultra-structural tissue integrity before and after subchronic memantine treatment. Further corroborating behavioural evidences were documented.
Results
Dose-dependent phMRI activation was observed in the prelimbic cortex following acute doses of memantine. Subchronic treatment revealed significant effects in the hippocampus, cingulate, prelimbic and retrosplenial cortices. Decreases in FC amongst the hippocampal and frontal cortical structures (prelimbic, cingulate) were apparent through rs-fMRI investigation, indicating a loss of connectivity. Diffusion kurtosis MRI showed decreases in fractional anisotropy and mean diffusivity changes, suggesting ultra-structural changes in the hippocampus and cingulate cortex. Limited behavioural assessment suggested that memantine induced behavioural effects comparable to other NMDA antagonists as measured by locomotor hyperactivity and that the effects could be reversed by antipsychotic drugs.
Conclusion
Our findings substantiate the hypothesis that repeated NMDA receptor blockade with nonspecific, noncompetitive NMDA antagonists may lead to functional and ultra-structural alterations, particularly in the hippocampus and cingulate cortex. These changes may underlie the behavioural effects. Furthermore, the present findings underscore the utility and the translational potential of multimodal MR imaging and acute/subchronic memantine model in the search for novel disease-modifying treatments for schizophrenia. |
| doi_str_mv | 10.1007/s00213-013-2966-3 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_proqu</sourceid><recordid>TN_cdi_proquest_miscellaneous_1356935747</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A337619261</galeid><sourcerecordid>A337619261</sourcerecordid><originalsourceid>FETCH-LOGICAL-c542t-90a8caaad4b7b0b5f940d16690ad003f344f195a1b4e8f8d16e453587ed00e303</originalsourceid><addsrcrecordid>eNp1kdtqFTEUhoModlt9AG8k4I03o8kkmYN3pXgoVAQP1yGTrNlNmUlqDoX9Nj6qa9z1gGAghGR9_59k_YQ85ewlZ6x_lRlruWgYznbsukbcIzsuRdu0rG_vkx1jQjSCq-GEPMr5muGQg3xITlohlFSC78j3z3WyVykGb-kKqwnFB6A-uGrBURuDrSlBKHSuwRYfg1mo8xkLAXB_68uBmuCoWQokVNSlJNPkkqotNSFcfM51cyywTxvtAy1XQFN0m-2UjA-vaYJbMAvqpwNd0cOv0aH4w6eLx-TBbJYMT-7WU_L17Zsv5--by4_vLs7PLhurZFuakZnBGmOcnPqJTWoeJXO86_DcYRtmIeXMR2X4JGGYBywBNkANPWAZBBOn5MXR9ybFbxVy0St-E5bFBIg1ay5UNwrVyx7R5_-g17Em7MxPSgo5Dqr7Q-3xY9qHOWJn7Gaqz4ToOz62HUeKHymbYs4JZn2T_GrSQXOmt5D1MWSNIestZC1Q8-zu_jqt4H4rfqWKQHsEMpbCHtJfD_yv6w9ZdbQ2</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1354349856</pqid></control><display><type>article</type><title>Subchronic memantine induced concurrent functional disconnectivity and altered ultra-structural tissue integrity in the rodent brain: revealed by multimodal MRI</title><source>MEDLINE</source><source>Springer Nature - Complete Springer Journals</source><creator>Sekar, S. ; Jonckers, E. ; Verhoye, M. ; Willems, R. ; Veraart, J. ; Van Audekerke, J. ; Couto, J. ; Giugliano, M. ; Wuyts, K. ; Dedeurwaerdere, S. ; Sijbers, J. ; Mackie, C. ; Ver Donck, L. ; Steckler, T. ; Van der Linden, A.</creator><creatorcontrib>Sekar, S. ; Jonckers, E. ; Verhoye, M. ; Willems, R. ; Veraart, J. ; Van Audekerke, J. ; Couto, J. ; Giugliano, M. ; Wuyts, K. ; Dedeurwaerdere, S. ; Sijbers, J. ; Mackie, C. ; Ver Donck, L. ; Steckler, T. ; Van der Linden, A.</creatorcontrib><description>Background
An effective NMDA antagonist imaging model may find key utility in advancing schizophrenia drug discovery research. We investigated effects of subchronic treatment with the NMDA antagonist memantine by using behavioural observation and multimodal MRI.
Methods
Pharmacological MRI (phMRI) was used to map the neuroanatomical binding sites of memantine after acute and subchronic treatment. Resting state fMRI (rs-fMRI) and diffusion MRI were used to study the changes in functional connectivity (FC) and ultra-structural tissue integrity before and after subchronic memantine treatment. Further corroborating behavioural evidences were documented.
Results
Dose-dependent phMRI activation was observed in the prelimbic cortex following acute doses of memantine. Subchronic treatment revealed significant effects in the hippocampus, cingulate, prelimbic and retrosplenial cortices. Decreases in FC amongst the hippocampal and frontal cortical structures (prelimbic, cingulate) were apparent through rs-fMRI investigation, indicating a loss of connectivity. Diffusion kurtosis MRI showed decreases in fractional anisotropy and mean diffusivity changes, suggesting ultra-structural changes in the hippocampus and cingulate cortex. Limited behavioural assessment suggested that memantine induced behavioural effects comparable to other NMDA antagonists as measured by locomotor hyperactivity and that the effects could be reversed by antipsychotic drugs.
Conclusion
Our findings substantiate the hypothesis that repeated NMDA receptor blockade with nonspecific, noncompetitive NMDA antagonists may lead to functional and ultra-structural alterations, particularly in the hippocampus and cingulate cortex. These changes may underlie the behavioural effects. Furthermore, the present findings underscore the utility and the translational potential of multimodal MR imaging and acute/subchronic memantine model in the search for novel disease-modifying treatments for schizophrenia.</description><identifier>ISSN: 0033-3158</identifier><identifier>EISSN: 1432-2072</identifier><identifier>DOI: 10.1007/s00213-013-2966-3</identifier><identifier>PMID: 23354531</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer-Verlag</publisher><subject>Animal models ; Animals ; Behavior ; Biomedical and Life Sciences ; Biomedicine ; Brain ; Brain - drug effects ; Brain - metabolism ; Brain - ultrastructure ; Brain Mapping ; Care and treatment ; Dose-Response Relationship, Drug ; Drug therapy ; Excitatory Amino Acid Antagonists - administration & dosage ; Excitatory Amino Acid Antagonists - pharmacokinetics ; Excitatory Amino Acid Antagonists - pharmacology ; Magnetic resonance imaging ; Magnetic Resonance Imaging - methods ; Male ; Memantine - administration & dosage ; Memantine - pharmacokinetics ; Memantine - pharmacology ; Methyl aspartate ; Motor Activity - drug effects ; Multimodal Imaging - methods ; Neurosciences ; NMR ; Nuclear magnetic resonance ; Original Investigation ; Pharmacology/Toxicology ; Properties ; Psychiatry ; Psychological aspects ; Rats ; Rats, Inbred Strains ; Rattus ; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors ; Rodents ; Schizophrenia</subject><ispartof>Psychopharmacology, 2013-06, Vol.227 (3), p.479-491</ispartof><rights>Springer-Verlag Berlin Heidelberg 2013</rights><rights>COPYRIGHT 2013 Springer</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c542t-90a8caaad4b7b0b5f940d16690ad003f344f195a1b4e8f8d16e453587ed00e303</citedby><cites>FETCH-LOGICAL-c542t-90a8caaad4b7b0b5f940d16690ad003f344f195a1b4e8f8d16e453587ed00e303</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00213-013-2966-3$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00213-013-2966-3$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23354531$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sekar, S.</creatorcontrib><creatorcontrib>Jonckers, E.</creatorcontrib><creatorcontrib>Verhoye, M.</creatorcontrib><creatorcontrib>Willems, R.</creatorcontrib><creatorcontrib>Veraart, J.</creatorcontrib><creatorcontrib>Van Audekerke, J.</creatorcontrib><creatorcontrib>Couto, J.</creatorcontrib><creatorcontrib>Giugliano, M.</creatorcontrib><creatorcontrib>Wuyts, K.</creatorcontrib><creatorcontrib>Dedeurwaerdere, S.</creatorcontrib><creatorcontrib>Sijbers, J.</creatorcontrib><creatorcontrib>Mackie, C.</creatorcontrib><creatorcontrib>Ver Donck, L.</creatorcontrib><creatorcontrib>Steckler, T.</creatorcontrib><creatorcontrib>Van der Linden, A.</creatorcontrib><title>Subchronic memantine induced concurrent functional disconnectivity and altered ultra-structural tissue integrity in the rodent brain: revealed by multimodal MRI</title><title>Psychopharmacology</title><addtitle>Psychopharmacology</addtitle><addtitle>Psychopharmacology (Berl)</addtitle><description>Background
An effective NMDA antagonist imaging model may find key utility in advancing schizophrenia drug discovery research. We investigated effects of subchronic treatment with the NMDA antagonist memantine by using behavioural observation and multimodal MRI.
Methods
Pharmacological MRI (phMRI) was used to map the neuroanatomical binding sites of memantine after acute and subchronic treatment. Resting state fMRI (rs-fMRI) and diffusion MRI were used to study the changes in functional connectivity (FC) and ultra-structural tissue integrity before and after subchronic memantine treatment. Further corroborating behavioural evidences were documented.
Results
Dose-dependent phMRI activation was observed in the prelimbic cortex following acute doses of memantine. Subchronic treatment revealed significant effects in the hippocampus, cingulate, prelimbic and retrosplenial cortices. Decreases in FC amongst the hippocampal and frontal cortical structures (prelimbic, cingulate) were apparent through rs-fMRI investigation, indicating a loss of connectivity. Diffusion kurtosis MRI showed decreases in fractional anisotropy and mean diffusivity changes, suggesting ultra-structural changes in the hippocampus and cingulate cortex. Limited behavioural assessment suggested that memantine induced behavioural effects comparable to other NMDA antagonists as measured by locomotor hyperactivity and that the effects could be reversed by antipsychotic drugs.
Conclusion
Our findings substantiate the hypothesis that repeated NMDA receptor blockade with nonspecific, noncompetitive NMDA antagonists may lead to functional and ultra-structural alterations, particularly in the hippocampus and cingulate cortex. These changes may underlie the behavioural effects. Furthermore, the present findings underscore the utility and the translational potential of multimodal MR imaging and acute/subchronic memantine model in the search for novel disease-modifying treatments for schizophrenia.</description><subject>Animal models</subject><subject>Animals</subject><subject>Behavior</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Brain</subject><subject>Brain - drug effects</subject><subject>Brain - metabolism</subject><subject>Brain - ultrastructure</subject><subject>Brain Mapping</subject><subject>Care and treatment</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug therapy</subject><subject>Excitatory Amino Acid Antagonists - administration & dosage</subject><subject>Excitatory Amino Acid Antagonists - pharmacokinetics</subject><subject>Excitatory Amino Acid Antagonists - pharmacology</subject><subject>Magnetic resonance imaging</subject><subject>Magnetic Resonance Imaging - methods</subject><subject>Male</subject><subject>Memantine - administration & dosage</subject><subject>Memantine - pharmacokinetics</subject><subject>Memantine - pharmacology</subject><subject>Methyl aspartate</subject><subject>Motor Activity - drug effects</subject><subject>Multimodal Imaging - methods</subject><subject>Neurosciences</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Original Investigation</subject><subject>Pharmacology/Toxicology</subject><subject>Properties</subject><subject>Psychiatry</subject><subject>Psychological aspects</subject><subject>Rats</subject><subject>Rats, Inbred Strains</subject><subject>Rattus</subject><subject>Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors</subject><subject>Rodents</subject><subject>Schizophrenia</subject><issn>0033-3158</issn><issn>1432-2072</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kdtqFTEUhoModlt9AG8k4I03o8kkmYN3pXgoVAQP1yGTrNlNmUlqDoX9Nj6qa9z1gGAghGR9_59k_YQ85ewlZ6x_lRlruWgYznbsukbcIzsuRdu0rG_vkx1jQjSCq-GEPMr5muGQg3xITlohlFSC78j3z3WyVykGb-kKqwnFB6A-uGrBURuDrSlBKHSuwRYfg1mo8xkLAXB_68uBmuCoWQokVNSlJNPkkqotNSFcfM51cyywTxvtAy1XQFN0m-2UjA-vaYJbMAvqpwNd0cOv0aH4w6eLx-TBbJYMT-7WU_L17Zsv5--by4_vLs7PLhurZFuakZnBGmOcnPqJTWoeJXO86_DcYRtmIeXMR2X4JGGYBywBNkANPWAZBBOn5MXR9ybFbxVy0St-E5bFBIg1ay5UNwrVyx7R5_-g17Em7MxPSgo5Dqr7Q-3xY9qHOWJn7Gaqz4ToOz62HUeKHymbYs4JZn2T_GrSQXOmt5D1MWSNIestZC1Q8-zu_jqt4H4rfqWKQHsEMpbCHtJfD_yv6w9ZdbQ2</recordid><startdate>20130601</startdate><enddate>20130601</enddate><creator>Sekar, S.</creator><creator>Jonckers, E.</creator><creator>Verhoye, M.</creator><creator>Willems, R.</creator><creator>Veraart, J.</creator><creator>Van Audekerke, J.</creator><creator>Couto, J.</creator><creator>Giugliano, M.</creator><creator>Wuyts, K.</creator><creator>Dedeurwaerdere, S.</creator><creator>Sijbers, J.</creator><creator>Mackie, C.</creator><creator>Ver Donck, L.</creator><creator>Steckler, T.</creator><creator>Van der Linden, A.</creator><general>Springer-Verlag</general><general>Springer</general><general>Springer Nature B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QG</scope><scope>7QR</scope><scope>7RV</scope><scope>7TK</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>88G</scope><scope>8AO</scope><scope>8FD</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>M2M</scope><scope>NAPCQ</scope><scope>P64</scope><scope>PHGZM</scope><scope>PHGZT</scope><scope>PJZUB</scope><scope>PKEHL</scope><scope>PPXIY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PSYQQ</scope><scope>Q9U</scope></search><sort><creationdate>20130601</creationdate><title>Subchronic memantine induced concurrent functional disconnectivity and altered ultra-structural tissue integrity in the rodent brain: revealed by multimodal MRI</title><author>Sekar, S. ; Jonckers, E. ; Verhoye, M. ; Willems, R. ; Veraart, J. ; Van Audekerke, J. ; Couto, J. ; Giugliano, M. ; Wuyts, K. ; Dedeurwaerdere, S. ; Sijbers, J. ; Mackie, C. ; Ver Donck, L. ; Steckler, T. ; Van der Linden, A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c542t-90a8caaad4b7b0b5f940d16690ad003f344f195a1b4e8f8d16e453587ed00e303</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animal models</topic><topic>Animals</topic><topic>Behavior</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Brain</topic><topic>Brain - drug effects</topic><topic>Brain - metabolism</topic><topic>Brain - ultrastructure</topic><topic>Brain Mapping</topic><topic>Care and treatment</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug therapy</topic><topic>Excitatory Amino Acid Antagonists - administration & dosage</topic><topic>Excitatory Amino Acid Antagonists - pharmacokinetics</topic><topic>Excitatory Amino Acid Antagonists - pharmacology</topic><topic>Magnetic resonance imaging</topic><topic>Magnetic Resonance Imaging - methods</topic><topic>Male</topic><topic>Memantine - administration & dosage</topic><topic>Memantine - pharmacokinetics</topic><topic>Memantine - pharmacology</topic><topic>Methyl aspartate</topic><topic>Motor Activity - drug effects</topic><topic>Multimodal Imaging - methods</topic><topic>Neurosciences</topic><topic>NMR</topic><topic>Nuclear magnetic resonance</topic><topic>Original Investigation</topic><topic>Pharmacology/Toxicology</topic><topic>Properties</topic><topic>Psychiatry</topic><topic>Psychological aspects</topic><topic>Rats</topic><topic>Rats, Inbred Strains</topic><topic>Rattus</topic><topic>Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors</topic><topic>Rodents</topic><topic>Schizophrenia</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sekar, S.</creatorcontrib><creatorcontrib>Jonckers, E.</creatorcontrib><creatorcontrib>Verhoye, M.</creatorcontrib><creatorcontrib>Willems, R.</creatorcontrib><creatorcontrib>Veraart, J.</creatorcontrib><creatorcontrib>Van Audekerke, J.</creatorcontrib><creatorcontrib>Couto, J.</creatorcontrib><creatorcontrib>Giugliano, M.</creatorcontrib><creatorcontrib>Wuyts, K.</creatorcontrib><creatorcontrib>Dedeurwaerdere, S.</creatorcontrib><creatorcontrib>Sijbers, J.</creatorcontrib><creatorcontrib>Mackie, C.</creatorcontrib><creatorcontrib>Ver Donck, L.</creatorcontrib><creatorcontrib>Steckler, T.</creatorcontrib><creatorcontrib>Van der Linden, A.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>Psychology Database (Alumni)</collection><collection>ProQuest Pharma Collection</collection><collection>Technology Research Database</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>ProQuest Central</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>ProQuest Psychology</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest Central (New)</collection><collection>ProQuest One Academic (New)</collection><collection>ProQuest Health & Medical Research Collection</collection><collection>ProQuest One Academic Middle East (New)</collection><collection>ProQuest One Health & Nursing</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest One Psychology</collection><collection>ProQuest Central Basic</collection><jtitle>Psychopharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sekar, S.</au><au>Jonckers, E.</au><au>Verhoye, M.</au><au>Willems, R.</au><au>Veraart, J.</au><au>Van Audekerke, J.</au><au>Couto, J.</au><au>Giugliano, M.</au><au>Wuyts, K.</au><au>Dedeurwaerdere, S.</au><au>Sijbers, J.</au><au>Mackie, C.</au><au>Ver Donck, L.</au><au>Steckler, T.</au><au>Van der Linden, A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Subchronic memantine induced concurrent functional disconnectivity and altered ultra-structural tissue integrity in the rodent brain: revealed by multimodal MRI</atitle><jtitle>Psychopharmacology</jtitle><stitle>Psychopharmacology</stitle><addtitle>Psychopharmacology (Berl)</addtitle><date>2013-06-01</date><risdate>2013</risdate><volume>227</volume><issue>3</issue><spage>479</spage><epage>491</epage><pages>479-491</pages><issn>0033-3158</issn><eissn>1432-2072</eissn><abstract>Background
An effective NMDA antagonist imaging model may find key utility in advancing schizophrenia drug discovery research. We investigated effects of subchronic treatment with the NMDA antagonist memantine by using behavioural observation and multimodal MRI.
Methods
Pharmacological MRI (phMRI) was used to map the neuroanatomical binding sites of memantine after acute and subchronic treatment. Resting state fMRI (rs-fMRI) and diffusion MRI were used to study the changes in functional connectivity (FC) and ultra-structural tissue integrity before and after subchronic memantine treatment. Further corroborating behavioural evidences were documented.
Results
Dose-dependent phMRI activation was observed in the prelimbic cortex following acute doses of memantine. Subchronic treatment revealed significant effects in the hippocampus, cingulate, prelimbic and retrosplenial cortices. Decreases in FC amongst the hippocampal and frontal cortical structures (prelimbic, cingulate) were apparent through rs-fMRI investigation, indicating a loss of connectivity. Diffusion kurtosis MRI showed decreases in fractional anisotropy and mean diffusivity changes, suggesting ultra-structural changes in the hippocampus and cingulate cortex. Limited behavioural assessment suggested that memantine induced behavioural effects comparable to other NMDA antagonists as measured by locomotor hyperactivity and that the effects could be reversed by antipsychotic drugs.
Conclusion
Our findings substantiate the hypothesis that repeated NMDA receptor blockade with nonspecific, noncompetitive NMDA antagonists may lead to functional and ultra-structural alterations, particularly in the hippocampus and cingulate cortex. These changes may underlie the behavioural effects. Furthermore, the present findings underscore the utility and the translational potential of multimodal MR imaging and acute/subchronic memantine model in the search for novel disease-modifying treatments for schizophrenia.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer-Verlag</pub><pmid>23354531</pmid><doi>10.1007/s00213-013-2966-3</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Psychopharmacology, 2013-06, Vol.227 (3), p.479-491 |
| issn | 0033-3158 1432-2072 |
| language | eng |
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| source | MEDLINE; Springer Nature - Complete Springer Journals |
| subjects | Animal models Animals Behavior Biomedical and Life Sciences Biomedicine Brain Brain - drug effects Brain - metabolism Brain - ultrastructure Brain Mapping Care and treatment Dose-Response Relationship, Drug Drug therapy Excitatory Amino Acid Antagonists - administration & dosage Excitatory Amino Acid Antagonists - pharmacokinetics Excitatory Amino Acid Antagonists - pharmacology Magnetic resonance imaging Magnetic Resonance Imaging - methods Male Memantine - administration & dosage Memantine - pharmacokinetics Memantine - pharmacology Methyl aspartate Motor Activity - drug effects Multimodal Imaging - methods Neurosciences NMR Nuclear magnetic resonance Original Investigation Pharmacology/Toxicology Properties Psychiatry Psychological aspects Rats Rats, Inbred Strains Rattus Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors Rodents Schizophrenia |
| title | Subchronic memantine induced concurrent functional disconnectivity and altered ultra-structural tissue integrity in the rodent brain: revealed by multimodal MRI |
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