Reversing cocaine-induced synaptic potentiation provides enduring protection from relapse
Cocaine addiction remains without an effective pharmacotherapy and is characterized by an inability of addicts to inhibit relapse to drug use. Vulnerability to relapse arises from an enduring impairment in cognitive control of motivated behavior, manifested in part by dysregulated synaptic potentiat...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2011-01, Vol.108 (1), p.385-390 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Moussawi, Khaled Zhou, Wenhua Shen, Haowei Reichel, Carmela M See, Ronald E Carr, David B Kalivas, Peter W |
| description | Cocaine addiction remains without an effective pharmacotherapy and is characterized by an inability of addicts to inhibit relapse to drug use. Vulnerability to relapse arises from an enduring impairment in cognitive control of motivated behavior, manifested in part by dysregulated synaptic potentiation and extracellular glutamate homeostasis in the projection from the prefrontal cortex to the nucleus accumbens. Here we show in rats trained to self-administer cocaine that the enduring cocaine-induced changes in synaptic potentiation and glutamate homeostasis are mechanistically linked through group II metabotropic glutamate receptor signaling. The enduring cocaine-induced changes in measures of cortico-accumbens synaptic and glial transmission were restored to predrug parameters for at least 2 wk after discontinuing chronic treatment with the cystine prodrug, N-acetylcysteine. N-acetylcysteine produced these changes by inducing an enduring restoration of nonsynaptic glutamatergic tone onto metabotropic glutamate receptors. The long-lasting pharmacological restoration of cocaine-induced glutamatergic adaptations by chronic N-acetylcysteine also caused enduring inhibition of cocaine-seeking in an animal model of relapse. These data mechanistically link nonsynaptic glutamate to cocaine-induced adaptations in excitatory transmission and demonstrate a mechanism to chronically restore prefrontal to accumbens transmission and thereby inhibit relapse in an animal model. |
| doi_str_mv | 10.1073/pnas.1011265108 |
| format | Article |
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Vulnerability to relapse arises from an enduring impairment in cognitive control of motivated behavior, manifested in part by dysregulated synaptic potentiation and extracellular glutamate homeostasis in the projection from the prefrontal cortex to the nucleus accumbens. Here we show in rats trained to self-administer cocaine that the enduring cocaine-induced changes in synaptic potentiation and glutamate homeostasis are mechanistically linked through group II metabotropic glutamate receptor signaling. The enduring cocaine-induced changes in measures of cortico-accumbens synaptic and glial transmission were restored to predrug parameters for at least 2 wk after discontinuing chronic treatment with the cystine prodrug, N-acetylcysteine. N-acetylcysteine produced these changes by inducing an enduring restoration of nonsynaptic glutamatergic tone onto metabotropic glutamate receptors. The long-lasting pharmacological restoration of cocaine-induced glutamatergic adaptations by chronic N-acetylcysteine also caused enduring inhibition of cocaine-seeking in an animal model of relapse. These data mechanistically link nonsynaptic glutamate to cocaine-induced adaptations in excitatory transmission and demonstrate a mechanism to chronically restore prefrontal to accumbens transmission and thereby inhibit relapse in an animal model.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1011265108</identifier><identifier>PMID: 21173236</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Acetylcysteine ; Acetylcysteine - pharmacology ; Adaptations ; Addiction ; Addicts ; Animal models ; Animals ; Behavioral neuroscience ; Biological Sciences ; Chromatography, High Pressure Liquid ; Cocaine ; Cocaine-Related Disorders - drug therapy ; Cognitive ability ; Cortex (prefrontal) ; Data processing ; Drug abuse ; Drug addiction ; Drug therapy ; Drug use ; Glutamic Acid - metabolism ; Glutamic acid receptors ; Glutamic acid receptors (metabotropic) ; Homeostasis ; Homeostasis - drug effects ; Homeostasis - physiology ; Long-Term Potentiation - drug effects ; Metabotropic glutamate receptors ; Microdialysis ; Motivation ; Nucleus accumbens ; Nucleus Accumbens - physiology ; Patch-Clamp Techniques ; Pharmacology ; Potentiation ; Prefrontal cortex ; Prefrontal Cortex - physiology ; prodrugs ; Rats ; Receptors, Metabotropic Glutamate - metabolism ; Relapse ; Secondary Prevention ; Signal Transduction - drug effects ; Signal Transduction - physiology ; Synaptic transmission ; Synaptic Transmission - drug effects ; Vehicles</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2011-01, Vol.108 (1), p.385-390</ispartof><rights>Copyright National Academy of Sciences Jan 4, 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c585t-b7cfd9ef03652bdc1f0cfc13c31f0bb1c79460277b305c5d28ccb5a08c60e1dc3</citedby><cites>FETCH-LOGICAL-c585t-b7cfd9ef03652bdc1f0cfc13c31f0bb1c79460277b305c5d28ccb5a08c60e1dc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/108/1.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/25770782$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/25770782$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,315,728,781,785,804,886,27929,27930,53796,53798,58022,58255</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21173236$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Moussawi, Khaled</creatorcontrib><creatorcontrib>Zhou, Wenhua</creatorcontrib><creatorcontrib>Shen, Haowei</creatorcontrib><creatorcontrib>Reichel, Carmela M</creatorcontrib><creatorcontrib>See, Ronald E</creatorcontrib><creatorcontrib>Carr, David B</creatorcontrib><creatorcontrib>Kalivas, Peter W</creatorcontrib><title>Reversing cocaine-induced synaptic potentiation provides enduring protection from relapse</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Cocaine addiction remains without an effective pharmacotherapy and is characterized by an inability of addicts to inhibit relapse to drug use. Vulnerability to relapse arises from an enduring impairment in cognitive control of motivated behavior, manifested in part by dysregulated synaptic potentiation and extracellular glutamate homeostasis in the projection from the prefrontal cortex to the nucleus accumbens. Here we show in rats trained to self-administer cocaine that the enduring cocaine-induced changes in synaptic potentiation and glutamate homeostasis are mechanistically linked through group II metabotropic glutamate receptor signaling. The enduring cocaine-induced changes in measures of cortico-accumbens synaptic and glial transmission were restored to predrug parameters for at least 2 wk after discontinuing chronic treatment with the cystine prodrug, N-acetylcysteine. N-acetylcysteine produced these changes by inducing an enduring restoration of nonsynaptic glutamatergic tone onto metabotropic glutamate receptors. The long-lasting pharmacological restoration of cocaine-induced glutamatergic adaptations by chronic N-acetylcysteine also caused enduring inhibition of cocaine-seeking in an animal model of relapse. These data mechanistically link nonsynaptic glutamate to cocaine-induced adaptations in excitatory transmission and demonstrate a mechanism to chronically restore prefrontal to accumbens transmission and thereby inhibit relapse in an animal model.</description><subject>Acetylcysteine</subject><subject>Acetylcysteine - pharmacology</subject><subject>Adaptations</subject><subject>Addiction</subject><subject>Addicts</subject><subject>Animal models</subject><subject>Animals</subject><subject>Behavioral neuroscience</subject><subject>Biological Sciences</subject><subject>Chromatography, High Pressure Liquid</subject><subject>Cocaine</subject><subject>Cocaine-Related Disorders - drug therapy</subject><subject>Cognitive ability</subject><subject>Cortex (prefrontal)</subject><subject>Data processing</subject><subject>Drug abuse</subject><subject>Drug addiction</subject><subject>Drug therapy</subject><subject>Drug use</subject><subject>Glutamic Acid - metabolism</subject><subject>Glutamic acid receptors</subject><subject>Glutamic acid receptors (metabotropic)</subject><subject>Homeostasis</subject><subject>Homeostasis - drug effects</subject><subject>Homeostasis - physiology</subject><subject>Long-Term Potentiation - drug effects</subject><subject>Metabotropic glutamate receptors</subject><subject>Microdialysis</subject><subject>Motivation</subject><subject>Nucleus accumbens</subject><subject>Nucleus Accumbens - physiology</subject><subject>Patch-Clamp Techniques</subject><subject>Pharmacology</subject><subject>Potentiation</subject><subject>Prefrontal cortex</subject><subject>Prefrontal Cortex - physiology</subject><subject>prodrugs</subject><subject>Rats</subject><subject>Receptors, Metabotropic Glutamate - metabolism</subject><subject>Relapse</subject><subject>Secondary Prevention</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - physiology</subject><subject>Synaptic transmission</subject><subject>Synaptic Transmission - drug effects</subject><subject>Vehicles</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkc1v1DAQxS1ERbeFMycg6oVT6NiOY-eChKoWkCohAT1wspyJs3iVtYOdrNT_HoddutCTR36_9zQfhLyk8I6C5JejNylXlLJaUFBPyIpCQ8u6auApWQEwWaqKVafkLKUNADRCwTNyyiiVnPF6RX58tTsbk_PrAgMa523pfDej7Yp07804OSzGMFk_OTO54Isxhp3rbCpsxuLiyz-TxT9iH8O2iHYwY7LPyUlvhmRfHN5zcndz_f3qU3n75ePnqw-3JQolprKV2HeN7YHXgrUd0h6wR8qR56ptKcqmqvMcsuUgUHRMIbbCgMIaLO2Qn5P3-9xxbre2w9xqNIMeo9uaeK-Dcfp_xbufeh12mgOVVMkc8PYQEMOv2aZJb11COwzG2zAnreq8NQl8IS8ekZswR5-n04qxhlWqqTN0uYcwhpSi7R9aoaCXo-nlaPp4tOx4_e8ED_zfK2Xg1QFYnMc4panmShz1TZpCPPqFlCAVy_qbvd6boM06uqTvvjGgeQMNr4Ro-G9tV7LF</recordid><startdate>20110104</startdate><enddate>20110104</enddate><creator>Moussawi, Khaled</creator><creator>Zhou, Wenhua</creator><creator>Shen, Haowei</creator><creator>Reichel, Carmela M</creator><creator>See, Ronald E</creator><creator>Carr, David B</creator><creator>Kalivas, Peter W</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20110104</creationdate><title>Reversing cocaine-induced synaptic potentiation provides enduring protection from relapse</title><author>Moussawi, Khaled ; 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Vulnerability to relapse arises from an enduring impairment in cognitive control of motivated behavior, manifested in part by dysregulated synaptic potentiation and extracellular glutamate homeostasis in the projection from the prefrontal cortex to the nucleus accumbens. Here we show in rats trained to self-administer cocaine that the enduring cocaine-induced changes in synaptic potentiation and glutamate homeostasis are mechanistically linked through group II metabotropic glutamate receptor signaling. The enduring cocaine-induced changes in measures of cortico-accumbens synaptic and glial transmission were restored to predrug parameters for at least 2 wk after discontinuing chronic treatment with the cystine prodrug, N-acetylcysteine. N-acetylcysteine produced these changes by inducing an enduring restoration of nonsynaptic glutamatergic tone onto metabotropic glutamate receptors. The long-lasting pharmacological restoration of cocaine-induced glutamatergic adaptations by chronic N-acetylcysteine also caused enduring inhibition of cocaine-seeking in an animal model of relapse. These data mechanistically link nonsynaptic glutamate to cocaine-induced adaptations in excitatory transmission and demonstrate a mechanism to chronically restore prefrontal to accumbens transmission and thereby inhibit relapse in an animal model.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>21173236</pmid><doi>10.1073/pnas.1011265108</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Proceedings of the National Academy of Sciences - PNAS, 2011-01, Vol.108 (1), p.385-390 |
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| subjects | Acetylcysteine Acetylcysteine - pharmacology Adaptations Addiction Addicts Animal models Animals Behavioral neuroscience Biological Sciences Chromatography, High Pressure Liquid Cocaine Cocaine-Related Disorders - drug therapy Cognitive ability Cortex (prefrontal) Data processing Drug abuse Drug addiction Drug therapy Drug use Glutamic Acid - metabolism Glutamic acid receptors Glutamic acid receptors (metabotropic) Homeostasis Homeostasis - drug effects Homeostasis - physiology Long-Term Potentiation - drug effects Metabotropic glutamate receptors Microdialysis Motivation Nucleus accumbens Nucleus Accumbens - physiology Patch-Clamp Techniques Pharmacology Potentiation Prefrontal cortex Prefrontal Cortex - physiology prodrugs Rats Receptors, Metabotropic Glutamate - metabolism Relapse Secondary Prevention Signal Transduction - drug effects Signal Transduction - physiology Synaptic transmission Synaptic Transmission - drug effects Vehicles |
| title | Reversing cocaine-induced synaptic potentiation provides enduring protection from relapse |
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