GABA Transmission in the Nucleus Accumbens Is Altered after Withdrawal from Repeated Cocaine
Repeated cocaine causes enduring changes in dopamine and glutamate transmission in the nucleus accumbens, and dopamine and glutamate terminals synapse on GABAergic accumbens neurons. The present study demonstrates that there are changes in GABA transmission in the accumbens at 3 weeks after disconti...
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| Veröffentlicht in: | The Journal of neuroscience 2003-04, Vol.23 (8), p.3498-3505 |
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| creator | Xi, Zheng-Xiong Ramamoorthy, Sammanda Shen, Hui Lake, Russell Samuvel, Devadoss J Kalivas, Peter W |
| description | Repeated cocaine causes enduring changes in dopamine and glutamate transmission in the nucleus accumbens, and dopamine and glutamate terminals synapse on GABAergic accumbens neurons. The present study demonstrates that there are changes in GABA transmission in the accumbens at 3 weeks after discontinuing daily cocaine injections. No-net flux microdialysis revealed a significant increase in the basal levels of extracellular GABA in the accumbens of cocaine-treated rats. The elevated extracellular GABA was normalized by blocking voltage-dependent Na+ channels and provided increased tone on GABA(B) presynaptic autoreceptors and heteroreceptors because blocking GABA(B) receptors produced a greater elevation in extracellular GABA, dopamine, and glutamate in cocaine-treated compared with control subjects. For many G-protein-coupled receptors, increased agonist can cause receptor desensitization. Consistent with GABA(B) receptor desensitization, baclofen-stimulated GTPgammaS binding was reduced, and the reduction in G-protein coupling was accompanied by reduced Ser phosphorylation of the GABA(B2) receptor subunit. No effect by repeated cocaine was found in the levels of total GABA(B1) or GABA(B2) protein. Together, these data demonstrate that withdrawal from repeated cocaine treatment produces an increase in the basal levels of extracellular GABA in the accumbens that depends on neuronal activity. The increase may be mediated in part by functional desensitization of GABA(B) receptors, likely the result of diminished Ser phosphorylation of the GABA(B2) receptor. |
| doi_str_mv | 10.1523/jneurosci.23-08-03498.2003 |
| format | Article |
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The present study demonstrates that there are changes in GABA transmission in the accumbens at 3 weeks after discontinuing daily cocaine injections. No-net flux microdialysis revealed a significant increase in the basal levels of extracellular GABA in the accumbens of cocaine-treated rats. The elevated extracellular GABA was normalized by blocking voltage-dependent Na+ channels and provided increased tone on GABA(B) presynaptic autoreceptors and heteroreceptors because blocking GABA(B) receptors produced a greater elevation in extracellular GABA, dopamine, and glutamate in cocaine-treated compared with control subjects. For many G-protein-coupled receptors, increased agonist can cause receptor desensitization. Consistent with GABA(B) receptor desensitization, baclofen-stimulated GTPgammaS binding was reduced, and the reduction in G-protein coupling was accompanied by reduced Ser phosphorylation of the GABA(B2) receptor subunit. No effect by repeated cocaine was found in the levels of total GABA(B1) or GABA(B2) protein. Together, these data demonstrate that withdrawal from repeated cocaine treatment produces an increase in the basal levels of extracellular GABA in the accumbens that depends on neuronal activity. The increase may be mediated in part by functional desensitization of GABA(B) receptors, likely the result of diminished Ser phosphorylation of the GABA(B2) receptor.</description><identifier>ISSN: 0270-6474</identifier><identifier>ISSN: 1529-2401</identifier><identifier>EISSN: 1529-2401</identifier><identifier>DOI: 10.1523/jneurosci.23-08-03498.2003</identifier><identifier>PMID: 12716959</identifier><language>eng</language><publisher>United States: Soc Neuroscience</publisher><subject>Animals ; Binding, Competitive - drug effects ; Chronic Disease ; Cocaine - adverse effects ; Cocaine-Related Disorders - physiopathology ; Disease Models, Animal ; Dopamine - analysis ; Dopamine - metabolism ; Drug Administration Schedule ; Extracellular Space - chemistry ; Extracellular Space - metabolism ; GABA Agonists - pharmacology ; GABA Antagonists - pharmacology ; GABA-B Receptor Agonists ; GABA-B Receptor Antagonists ; gamma-Aminobutyric Acid - analysis ; gamma-Aminobutyric Acid - metabolism ; Glutamic Acid - analysis ; Glutamic Acid - metabolism ; Guanosine 5'-O-(3-Thiotriphosphate) - pharmacokinetics ; Male ; Microdialysis ; Nucleus Accumbens - drug effects ; Nucleus Accumbens - physiopathology ; Phosphorylation - drug effects ; Protein Subunits - agonists ; Protein Subunits - antagonists & inhibitors ; Protein Subunits - metabolism ; Rats ; Rats, Sprague-Dawley ; Receptors, GABA-B - metabolism ; Substance Withdrawal Syndrome - physiopathology ; Synaptic Transmission - drug effects</subject><ispartof>The Journal of neuroscience, 2003-04, Vol.23 (8), p.3498-3505</ispartof><rights>Copyright © 2003 Society for Neuroscience 2003</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c550t-63fffeaa84f835194d61202d9db02e8f08826c85da77e2051f312a52454e75b13</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742318/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742318/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12716959$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Xi, Zheng-Xiong</creatorcontrib><creatorcontrib>Ramamoorthy, Sammanda</creatorcontrib><creatorcontrib>Shen, Hui</creatorcontrib><creatorcontrib>Lake, Russell</creatorcontrib><creatorcontrib>Samuvel, Devadoss J</creatorcontrib><creatorcontrib>Kalivas, Peter W</creatorcontrib><title>GABA Transmission in the Nucleus Accumbens Is Altered after Withdrawal from Repeated Cocaine</title><title>The Journal of neuroscience</title><addtitle>J Neurosci</addtitle><description>Repeated cocaine causes enduring changes in dopamine and glutamate transmission in the nucleus accumbens, and dopamine and glutamate terminals synapse on GABAergic accumbens neurons. The present study demonstrates that there are changes in GABA transmission in the accumbens at 3 weeks after discontinuing daily cocaine injections. No-net flux microdialysis revealed a significant increase in the basal levels of extracellular GABA in the accumbens of cocaine-treated rats. The elevated extracellular GABA was normalized by blocking voltage-dependent Na+ channels and provided increased tone on GABA(B) presynaptic autoreceptors and heteroreceptors because blocking GABA(B) receptors produced a greater elevation in extracellular GABA, dopamine, and glutamate in cocaine-treated compared with control subjects. For many G-protein-coupled receptors, increased agonist can cause receptor desensitization. Consistent with GABA(B) receptor desensitization, baclofen-stimulated GTPgammaS binding was reduced, and the reduction in G-protein coupling was accompanied by reduced Ser phosphorylation of the GABA(B2) receptor subunit. No effect by repeated cocaine was found in the levels of total GABA(B1) or GABA(B2) protein. Together, these data demonstrate that withdrawal from repeated cocaine treatment produces an increase in the basal levels of extracellular GABA in the accumbens that depends on neuronal activity. The increase may be mediated in part by functional desensitization of GABA(B) receptors, likely the result of diminished Ser phosphorylation of the GABA(B2) receptor.</description><subject>Animals</subject><subject>Binding, Competitive - drug effects</subject><subject>Chronic Disease</subject><subject>Cocaine - adverse effects</subject><subject>Cocaine-Related Disorders - physiopathology</subject><subject>Disease Models, Animal</subject><subject>Dopamine - analysis</subject><subject>Dopamine - metabolism</subject><subject>Drug Administration Schedule</subject><subject>Extracellular Space - chemistry</subject><subject>Extracellular Space - metabolism</subject><subject>GABA Agonists - pharmacology</subject><subject>GABA Antagonists - pharmacology</subject><subject>GABA-B Receptor Agonists</subject><subject>GABA-B Receptor Antagonists</subject><subject>gamma-Aminobutyric Acid - analysis</subject><subject>gamma-Aminobutyric Acid - metabolism</subject><subject>Glutamic Acid - analysis</subject><subject>Glutamic Acid - metabolism</subject><subject>Guanosine 5'-O-(3-Thiotriphosphate) - pharmacokinetics</subject><subject>Male</subject><subject>Microdialysis</subject><subject>Nucleus Accumbens - drug effects</subject><subject>Nucleus Accumbens - physiopathology</subject><subject>Phosphorylation - drug effects</subject><subject>Protein Subunits - agonists</subject><subject>Protein Subunits - antagonists & inhibitors</subject><subject>Protein Subunits - metabolism</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, GABA-B - metabolism</subject><subject>Substance Withdrawal Syndrome - physiopathology</subject><subject>Synaptic Transmission - drug effects</subject><issn>0270-6474</issn><issn>1529-2401</issn><issn>1529-2401</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2003</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkU1v1DAQhi0EokvhLyCLA7cs_owdDkjLqpRFVSuVVlyQLK8zblzlY2snRP339dIVhROn0WieefXOvAi9o2RJJeMfbnuY4pBcWDJeEF0QLiq9ZITwZ2iRiapggtDnaEGYIkUplDhCr1K6JYQoQtVLdESZomUlqwX6ebr6vMJX0fapCymFocehx2MD-HxyLUwJr5ybui30CW9y044QocbW54p_hLGpo51ti30cOnwJO7BjHq8HZ0MPr9ELb9sEbw71GF1_Oblafy3OLk4369VZ4aQkY1Fy7z1Yq4XXXNJK1CVlhNVVvSUMtCdas9JpWVulgBFJPafMSiakACW3lB-jT4-6u2nbQe2gH6NtzS6GzsZ7M9hg_p30oTE3wy9TKsE41Vng_UEgDncTpNHkZzhoW9vDMCWjOJNEMfpfkOpK0Owugx8fQZeTShH8HzeUmH2K5tv5yfXlxff1xuSGaPM7RbNPMS-__fuep9VDbE82mnDTzCGCSZ1t24xTM89zFtRmL8cfABhtqKo</recordid><startdate>20030415</startdate><enddate>20030415</enddate><creator>Xi, Zheng-Xiong</creator><creator>Ramamoorthy, Sammanda</creator><creator>Shen, Hui</creator><creator>Lake, Russell</creator><creator>Samuvel, Devadoss J</creator><creator>Kalivas, Peter W</creator><general>Soc Neuroscience</general><general>Society for Neuroscience</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>7TK</scope><scope>7U7</scope><scope>C1K</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20030415</creationdate><title>GABA Transmission in the Nucleus Accumbens Is Altered after Withdrawal from Repeated Cocaine</title><author>Xi, Zheng-Xiong ; 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The present study demonstrates that there are changes in GABA transmission in the accumbens at 3 weeks after discontinuing daily cocaine injections. No-net flux microdialysis revealed a significant increase in the basal levels of extracellular GABA in the accumbens of cocaine-treated rats. The elevated extracellular GABA was normalized by blocking voltage-dependent Na+ channels and provided increased tone on GABA(B) presynaptic autoreceptors and heteroreceptors because blocking GABA(B) receptors produced a greater elevation in extracellular GABA, dopamine, and glutamate in cocaine-treated compared with control subjects. For many G-protein-coupled receptors, increased agonist can cause receptor desensitization. Consistent with GABA(B) receptor desensitization, baclofen-stimulated GTPgammaS binding was reduced, and the reduction in G-protein coupling was accompanied by reduced Ser phosphorylation of the GABA(B2) receptor subunit. No effect by repeated cocaine was found in the levels of total GABA(B1) or GABA(B2) protein. Together, these data demonstrate that withdrawal from repeated cocaine treatment produces an increase in the basal levels of extracellular GABA in the accumbens that depends on neuronal activity. The increase may be mediated in part by functional desensitization of GABA(B) receptors, likely the result of diminished Ser phosphorylation of the GABA(B2) receptor.</abstract><cop>United States</cop><pub>Soc Neuroscience</pub><pmid>12716959</pmid><doi>10.1523/jneurosci.23-08-03498.2003</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Binding, Competitive - drug effects Chronic Disease Cocaine - adverse effects Cocaine-Related Disorders - physiopathology Disease Models, Animal Dopamine - analysis Dopamine - metabolism Drug Administration Schedule Extracellular Space - chemistry Extracellular Space - metabolism GABA Agonists - pharmacology GABA Antagonists - pharmacology GABA-B Receptor Agonists GABA-B Receptor Antagonists gamma-Aminobutyric Acid - analysis gamma-Aminobutyric Acid - metabolism Glutamic Acid - analysis Glutamic Acid - metabolism Guanosine 5'-O-(3-Thiotriphosphate) - pharmacokinetics Male Microdialysis Nucleus Accumbens - drug effects Nucleus Accumbens - physiopathology Phosphorylation - drug effects Protein Subunits - agonists Protein Subunits - antagonists & inhibitors Protein Subunits - metabolism Rats Rats, Sprague-Dawley Receptors, GABA-B - metabolism Substance Withdrawal Syndrome - physiopathology Synaptic Transmission - drug effects |
| title | GABA Transmission in the Nucleus Accumbens Is Altered after Withdrawal from Repeated Cocaine |
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