Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice
The cannabis constituent cannabidiol (CBD) possesses anxiolytic and antipsychotic properties. We have previously shown that transmembrane domain neuregulin 1 mutant (Nrg1 TM HET) mice display altered neurobehavioural responses to the main psychoactive constituent of cannabis, Δ(9)-tetrahydrocannabin...
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| Veröffentlicht in: | PloS one 2012-04, Vol.7 (4), p.e34129 |
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| creator | Long, Leonora E Chesworth, Rose Huang, Xu-Feng Wong, Alexander Spiro, Adena McGregor, Iain S Arnold, Jonathon C Karl, Tim |
| description | The cannabis constituent cannabidiol (CBD) possesses anxiolytic and antipsychotic properties. We have previously shown that transmembrane domain neuregulin 1 mutant (Nrg1 TM HET) mice display altered neurobehavioural responses to the main psychoactive constituent of cannabis, Δ(9)-tetrahydrocannabinol. Here we investigated whether Nrg1 TM HET mice respond differently to CBD and whether CBD reverses schizophrenia-related phenotypes expressed by these mice. Adult male Nrg1 TM HET and wild type-like littermates (WT) received vehicle or CBD (1, 50 or 100 mg/kg i.p.) for 21 days. During treatment and 48 h after withdrawal we measured behaviour, whole blood CBD concentrations and autoradiographic receptor binding. Nrg1 HET mice displayed locomotor hyperactivity, PPI deficits and reduced 5-HT(2A) receptor binding density in the substantia nigra, but these phenotypes were not reversed by CBD. However, long-term CBD (50 and 100 mg/kg) selectively enhanced social interaction in Nrg1 TM HET mice. Furthermore, acute CBD (100 mg/kg) selectively increased PPI in Nrg1 TM HET mice, although tolerance to this effect was manifest upon repeated CBD administration. Long-term CBD (50 mg/kg) also selectively increased GABA(A) receptor binding in the granular retrosplenial cortex in Nrg1 TM HET mice and reduced 5-HT(2A) binding in the substantia nigra in WT mice. Nrg1 appears necessary for CBD-induced anxiolysis since only WT mice developed decreased anxiety-related behaviour with repeated CBD treatment. Altered pharmacokinetics in mutant mice could not explain our findings since no genotype differences existed in CBD blood concentrations. Here we demonstrate that Nrg1 modulates acute and long-term neurobehavioural effects of CBD, which does not reverse the schizophrenia-relevant phenotypes. |
| doi_str_mv | 10.1371/journal.pone.0034129 |
| format | Article |
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We have previously shown that transmembrane domain neuregulin 1 mutant (Nrg1 TM HET) mice display altered neurobehavioural responses to the main psychoactive constituent of cannabis, Δ(9)-tetrahydrocannabinol. Here we investigated whether Nrg1 TM HET mice respond differently to CBD and whether CBD reverses schizophrenia-related phenotypes expressed by these mice. Adult male Nrg1 TM HET and wild type-like littermates (WT) received vehicle or CBD (1, 50 or 100 mg/kg i.p.) for 21 days. During treatment and 48 h after withdrawal we measured behaviour, whole blood CBD concentrations and autoradiographic receptor binding. Nrg1 HET mice displayed locomotor hyperactivity, PPI deficits and reduced 5-HT(2A) receptor binding density in the substantia nigra, but these phenotypes were not reversed by CBD. However, long-term CBD (50 and 100 mg/kg) selectively enhanced social interaction in Nrg1 TM HET mice. Furthermore, acute CBD (100 mg/kg) selectively increased PPI in Nrg1 TM HET mice, although tolerance to this effect was manifest upon repeated CBD administration. Long-term CBD (50 mg/kg) also selectively increased GABA(A) receptor binding in the granular retrosplenial cortex in Nrg1 TM HET mice and reduced 5-HT(2A) binding in the substantia nigra in WT mice. Nrg1 appears necessary for CBD-induced anxiolysis since only WT mice developed decreased anxiety-related behaviour with repeated CBD treatment. Altered pharmacokinetics in mutant mice could not explain our findings since no genotype differences existed in CBD blood concentrations. Here we demonstrate that Nrg1 modulates acute and long-term neurobehavioural effects of CBD, which does not reverse the schizophrenia-relevant phenotypes.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0034129</identifier><identifier>PMID: 22509273</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Animals ; Antipsychotics ; Anxiety ; Anxiety - chemically induced ; Autoradiography ; Behavior, Animal - drug effects ; Behavior, Animal - physiology ; Binding ; Biology ; Blood ; Brain research ; Cannabidiol - blood ; Cannabidiol - pharmacology ; Cannabinoids ; Cannabis ; Cell Membrane - metabolism ; Chromatography ; Constituents ; Drug dosages ; Exploratory Behavior - drug effects ; Female ; Genotype & phenotype ; Genotypes ; Hyperactivity ; Locomotion - drug effects ; Male ; Marijuana ; Mass spectrometry ; Medicine ; Mental disorders ; Mice ; Mutation ; Neuregulin ; Neuregulin 1 ; Neuregulin-1 - chemistry ; Neuregulin-1 - genetics ; Neuregulin-1 - metabolism ; Neurosciences ; Pharmacokinetics ; Pharmacology ; Plasma ; Protein Structure, Tertiary ; Psychopharmacology ; Psychotropic drugs ; Receptor density ; Receptor, Serotonin, 5-HT2A - metabolism ; Rodents ; Schizophrenia ; Scientific imaging ; Sensory Gating - drug effects ; Serotonin S2 receptors ; Social aspects ; Social behavior ; Studies ; Substantia nigra ; Tetrahydrocannabinol ; Time Factors ; Tranquilizing drugs ; Transmembrane domains ; Withdrawal ; γ-Aminobutyric acid A receptors</subject><ispartof>PloS one, 2012-04, Vol.7 (4), p.e34129</ispartof><rights>COPYRIGHT 2012 Public Library of Science</rights><rights>2012 Long et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>Long et al. 2012</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6589-f6e00417f81595675dcb2a877ec7b353b5c0b88e0fed18818089c5dfa4d6ab5c3</citedby><cites>FETCH-LOGICAL-c6589-f6e00417f81595675dcb2a877ec7b353b5c0b88e0fed18818089c5dfa4d6ab5c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3317922/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3317922/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/22509273$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Hashimoto, Kenji</contributor><creatorcontrib>Long, Leonora E</creatorcontrib><creatorcontrib>Chesworth, Rose</creatorcontrib><creatorcontrib>Huang, Xu-Feng</creatorcontrib><creatorcontrib>Wong, Alexander</creatorcontrib><creatorcontrib>Spiro, Adena</creatorcontrib><creatorcontrib>McGregor, Iain S</creatorcontrib><creatorcontrib>Arnold, Jonathon C</creatorcontrib><creatorcontrib>Karl, Tim</creatorcontrib><title>Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The cannabis constituent cannabidiol (CBD) possesses anxiolytic and antipsychotic properties. We have previously shown that transmembrane domain neuregulin 1 mutant (Nrg1 TM HET) mice display altered neurobehavioural responses to the main psychoactive constituent of cannabis, Δ(9)-tetrahydrocannabinol. Here we investigated whether Nrg1 TM HET mice respond differently to CBD and whether CBD reverses schizophrenia-related phenotypes expressed by these mice. Adult male Nrg1 TM HET and wild type-like littermates (WT) received vehicle or CBD (1, 50 or 100 mg/kg i.p.) for 21 days. During treatment and 48 h after withdrawal we measured behaviour, whole blood CBD concentrations and autoradiographic receptor binding. Nrg1 HET mice displayed locomotor hyperactivity, PPI deficits and reduced 5-HT(2A) receptor binding density in the substantia nigra, but these phenotypes were not reversed by CBD. However, long-term CBD (50 and 100 mg/kg) selectively enhanced social interaction in Nrg1 TM HET mice. 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drug effects</subject><subject>Male</subject><subject>Marijuana</subject><subject>Mass spectrometry</subject><subject>Medicine</subject><subject>Mental disorders</subject><subject>Mice</subject><subject>Mutation</subject><subject>Neuregulin</subject><subject>Neuregulin 1</subject><subject>Neuregulin-1 - chemistry</subject><subject>Neuregulin-1 - genetics</subject><subject>Neuregulin-1 - metabolism</subject><subject>Neurosciences</subject><subject>Pharmacokinetics</subject><subject>Pharmacology</subject><subject>Plasma</subject><subject>Protein Structure, Tertiary</subject><subject>Psychopharmacology</subject><subject>Psychotropic drugs</subject><subject>Receptor density</subject><subject>Receptor, Serotonin, 5-HT2A - metabolism</subject><subject>Rodents</subject><subject>Schizophrenia</subject><subject>Scientific imaging</subject><subject>Sensory Gating - drug effects</subject><subject>Serotonin S2 receptors</subject><subject>Social aspects</subject><subject>Social behavior</subject><subject>Studies</subject><subject>Substantia nigra</subject><subject>Tetrahydrocannabinol</subject><subject>Time Factors</subject><subject>Tranquilizing drugs</subject><subject>Transmembrane domains</subject><subject>Withdrawal</subject><subject>γ-Aminobutyric acid A receptors</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2012</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkl1r2zAYhc3YWLtu_2BshkFhF8kky_q6GZR2H4FCYV-3QpZfJQq2lFpy2f79lMUtMWwwfCHx6jlH4vgUxUuMlphw_G4bxsHrbrkLHpYIkRpX8lFxiiWpFqxC5PHR_qR4FuMWIUoEY0-Lk6qiSFacnBb6ysXkvEmlh3EIDWz0ncvOuivBWjAplsGWRnuvG9e60JXOl2nQPvbQN3mFsg29zsO9HtZjl7e47MekfSp7Z-B58cTqLsKLaT0rvn_88O3y8-L65tPq8uJ6YRgVcmEZIFRjbgWmkjJOW9NUWnAOhjeEkoYa1AgByEKLhcACCWloa3XdMp0PyVnx-uC760JUUzpRVQhJxhASNBOrA9EGvVW7wfV6-KWCdurPIAxrpYfkTAeKSUPAmNoYRuoW48bUiFECLVgquWmy1_vptrHpoTXgcyjdzHR-4t1GrcOdIgRzWVXZ4M1kMITbEWL6x5Mnaq3zq5y3IZuZ3kWjLmrOcS2FEJla_oXKXwv5D-R-WJfnM8HbmSAzCX6mtR5jVKuvX_6fvfkxZ8-P2A3oLm1i6Mbkgo9zsD6AZggxDmAfksNI7et9n4ba11tN9c6yV8epP4ju-0x-AwqO9vk</recordid><startdate>20120403</startdate><enddate>20120403</enddate><creator>Long, Leonora E</creator><creator>Chesworth, Rose</creator><creator>Huang, Xu-Feng</creator><creator>Wong, Alexander</creator><creator>Spiro, Adena</creator><creator>McGregor, Iain S</creator><creator>Arnold, Jonathon C</creator><creator>Karl, Tim</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20120403</creationdate><title>Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice</title><author>Long, Leonora E ; Chesworth, Rose ; Huang, Xu-Feng ; Wong, Alexander ; Spiro, Adena ; McGregor, Iain S ; Arnold, Jonathon C ; Karl, Tim</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c6589-f6e00417f81595675dcb2a877ec7b353b5c0b88e0fed18818089c5dfa4d6ab5c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2012</creationdate><topic>Animals</topic><topic>Antipsychotics</topic><topic>Anxiety</topic><topic>Anxiety - 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We have previously shown that transmembrane domain neuregulin 1 mutant (Nrg1 TM HET) mice display altered neurobehavioural responses to the main psychoactive constituent of cannabis, Δ(9)-tetrahydrocannabinol. Here we investigated whether Nrg1 TM HET mice respond differently to CBD and whether CBD reverses schizophrenia-related phenotypes expressed by these mice. Adult male Nrg1 TM HET and wild type-like littermates (WT) received vehicle or CBD (1, 50 or 100 mg/kg i.p.) for 21 days. During treatment and 48 h after withdrawal we measured behaviour, whole blood CBD concentrations and autoradiographic receptor binding. Nrg1 HET mice displayed locomotor hyperactivity, PPI deficits and reduced 5-HT(2A) receptor binding density in the substantia nigra, but these phenotypes were not reversed by CBD. However, long-term CBD (50 and 100 mg/kg) selectively enhanced social interaction in Nrg1 TM HET mice. Furthermore, acute CBD (100 mg/kg) selectively increased PPI in Nrg1 TM HET mice, although tolerance to this effect was manifest upon repeated CBD administration. Long-term CBD (50 mg/kg) also selectively increased GABA(A) receptor binding in the granular retrosplenial cortex in Nrg1 TM HET mice and reduced 5-HT(2A) binding in the substantia nigra in WT mice. Nrg1 appears necessary for CBD-induced anxiolysis since only WT mice developed decreased anxiety-related behaviour with repeated CBD treatment. Altered pharmacokinetics in mutant mice could not explain our findings since no genotype differences existed in CBD blood concentrations. Here we demonstrate that Nrg1 modulates acute and long-term neurobehavioural effects of CBD, which does not reverse the schizophrenia-relevant phenotypes.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>22509273</pmid><doi>10.1371/journal.pone.0034129</doi><tpages>e34129</tpages><oa>free_for_read</oa></addata></record> |
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| language | eng |
| recordid | cdi_plos_journals_2009660085 |
| source | MEDLINE; Public Library of Science; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Animals Antipsychotics Anxiety Anxiety - chemically induced Autoradiography Behavior, Animal - drug effects Behavior, Animal - physiology Binding Biology Blood Brain research Cannabidiol - blood Cannabidiol - pharmacology Cannabinoids Cannabis Cell Membrane - metabolism Chromatography Constituents Drug dosages Exploratory Behavior - drug effects Female Genotype & phenotype Genotypes Hyperactivity Locomotion - drug effects Male Marijuana Mass spectrometry Medicine Mental disorders Mice Mutation Neuregulin Neuregulin 1 Neuregulin-1 - chemistry Neuregulin-1 - genetics Neuregulin-1 - metabolism Neurosciences Pharmacokinetics Pharmacology Plasma Protein Structure, Tertiary Psychopharmacology Psychotropic drugs Receptor density Receptor, Serotonin, 5-HT2A - metabolism Rodents Schizophrenia Scientific imaging Sensory Gating - drug effects Serotonin S2 receptors Social aspects Social behavior Studies Substantia nigra Tetrahydrocannabinol Time Factors Tranquilizing drugs Transmembrane domains Withdrawal γ-Aminobutyric acid A receptors |
| title | Distinct neurobehavioural effects of cannabidiol in transmembrane domain neuregulin 1 mutant mice |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-20T18%3A46%3A34IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Distinct%20neurobehavioural%20effects%20of%20cannabidiol%20in%20transmembrane%20domain%20neuregulin%201%20mutant%20mice&rft.jtitle=PloS%20one&rft.au=Long,%20Leonora%20E&rft.date=2012-04-03&rft.volume=7&rft.issue=4&rft.spage=e34129&rft.pages=e34129-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0034129&rft_dat=%3Cgale_plos_%3EA477149888%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2009660085&rft_id=info:pmid/22509273&rft_galeid=A477149888&rft_doaj_id=oai_doaj_org_article_69c3ecc4cc634d11bc40653edef597cb&rfr_iscdi=true |