DARPP-32 and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens
The medium spiny neurons of the nucleus accumbens receive both an excitatory glutamatergic input from forebrain and a dopaminergic input from the ventral tegmental area. This integration point may constitute a locus whereby the N -methyl- D -aspartate (NMDA)-subtype of glutamate receptors promotes d...
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| Veröffentlicht in: | Nature neuroscience 2002-07, Vol.5 (7), p.641-648 |
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| creator | Maldve, R. E. Zhang, T. A. Ferrani-Kile, K. Schreiber, S. S. Lippmann, M. J. Snyder, G. L. Fienberg, A. A. Leslie, S. W. Gonzales, R. A. Morrisett, R. A. |
| description | The medium spiny neurons of the nucleus accumbens receive both an excitatory glutamatergic input from forebrain and a dopaminergic input from the ventral tegmental area. This integration point may constitute a locus whereby the
N
-methyl-
D
-aspartate (NMDA)-subtype of glutamate receptors promotes drug reinforcement. Here we investigate how dopaminergic inputs alter the ethanol sensitivity of NMDA receptors in rats and mice and report that previous dopamine receptor-1 (D1) activation, culminating in dopamine and cAMP-regulated phosphoprotein-32 kD (DARPP-32) and NMDA receptor subunit-1 (NR1)-NMDA receptor phosphorylation, strongly decreases ethanol inhibition of NMDA responses. The regulation of ethanol sensitivity of NMDA receptors by D1 receptors was absent in DARPP-32 knockout mice. We propose that DARPP-32 mediated blunting of the response to ethanol subsequent to activation of ventral tegmental area dopaminergic neurons initiates molecular alterations that influence synaptic plasticity in this circuit, thereby promoting the development of ethanol reinforcement. |
| doi_str_mv | 10.1038/nn877 |
| format | Article |
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N
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-aspartate (NMDA)-subtype of glutamate receptors promotes drug reinforcement. Here we investigate how dopaminergic inputs alter the ethanol sensitivity of NMDA receptors in rats and mice and report that previous dopamine receptor-1 (D1) activation, culminating in dopamine and cAMP-regulated phosphoprotein-32 kD (DARPP-32) and NMDA receptor subunit-1 (NR1)-NMDA receptor phosphorylation, strongly decreases ethanol inhibition of NMDA responses. The regulation of ethanol sensitivity of NMDA receptors by D1 receptors was absent in DARPP-32 knockout mice. We propose that DARPP-32 mediated blunting of the response to ethanol subsequent to activation of ventral tegmental area dopaminergic neurons initiates molecular alterations that influence synaptic plasticity in this circuit, thereby promoting the development of ethanol reinforcement.</description><identifier>ISSN: 1097-6256</identifier><identifier>EISSN: 1546-1726</identifier><identifier>DOI: 10.1038/nn877</identifier><identifier>PMID: 12068305</identifier><identifier>CODEN: NANEFN</identifier><language>eng</language><publisher>New York: Nature Publishing Group US</publisher><subject>2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine - pharmacology ; Animal Genetics and Genomics ; Animals ; Behavioral Sciences ; Biological Techniques ; Biomedical and Life Sciences ; Biomedicine ; Cell nuclei ; Cyclic AMP - metabolism ; Cyclic AMP-Dependent Protein Kinases - metabolism ; Dopamine - metabolism ; Dopamine Agonists - pharmacology ; Dopamine and cAMP-Regulated Phosphoprotein 32 ; Ethanol - pharmacology ; In Vitro Techniques ; Mice ; Mice, Knockout ; Nerve Tissue Proteins ; Neurobiology ; Neuronal Plasticity - drug effects ; Neuronal Plasticity - physiology ; Neurosciences ; Neurotransmitter receptors ; Nucleus Accumbens - cytology ; Nucleus Accumbens - drug effects ; Nucleus Accumbens - metabolism ; Phosphoproteins - deficiency ; Phosphoproteins - genetics ; Phosphoproteins - metabolism ; Phosphorylation - drug effects ; Physiological aspects ; Rats ; Receptors, Dopamine D1 - metabolism ; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors ; Receptors, N-Methyl-D-Aspartate - drug effects ; Receptors, N-Methyl-D-Aspartate - metabolism ; Ventral Tegmental Area - physiology</subject><ispartof>Nature neuroscience, 2002-07, Vol.5 (7), p.641-648</ispartof><rights>Springer Nature America, Inc. 2002</rights><rights>COPYRIGHT 2002 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Jul 2002</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c533t-fd8448c2da226a1fe4b760611ea5241170c4801ea0855a37d4c839480973ecd53</citedby><cites>FETCH-LOGICAL-c533t-fd8448c2da226a1fe4b760611ea5241170c4801ea0855a37d4c839480973ecd53</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/nn877$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/nn877$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,777,781,27905,27906,41469,42538,51300</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/12068305$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Maldve, R. E.</creatorcontrib><creatorcontrib>Zhang, T. A.</creatorcontrib><creatorcontrib>Ferrani-Kile, K.</creatorcontrib><creatorcontrib>Schreiber, S. S.</creatorcontrib><creatorcontrib>Lippmann, M. J.</creatorcontrib><creatorcontrib>Snyder, G. L.</creatorcontrib><creatorcontrib>Fienberg, A. A.</creatorcontrib><creatorcontrib>Leslie, S. W.</creatorcontrib><creatorcontrib>Gonzales, R. A.</creatorcontrib><creatorcontrib>Morrisett, R. A.</creatorcontrib><title>DARPP-32 and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens</title><title>Nature neuroscience</title><addtitle>Nat Neurosci</addtitle><addtitle>Nat Neurosci</addtitle><description>The medium spiny neurons of the nucleus accumbens receive both an excitatory glutamatergic input from forebrain and a dopaminergic input from the ventral tegmental area. This integration point may constitute a locus whereby the
N
-methyl-
D
-aspartate (NMDA)-subtype of glutamate receptors promotes drug reinforcement. Here we investigate how dopaminergic inputs alter the ethanol sensitivity of NMDA receptors in rats and mice and report that previous dopamine receptor-1 (D1) activation, culminating in dopamine and cAMP-regulated phosphoprotein-32 kD (DARPP-32) and NMDA receptor subunit-1 (NR1)-NMDA receptor phosphorylation, strongly decreases ethanol inhibition of NMDA responses. The regulation of ethanol sensitivity of NMDA receptors by D1 receptors was absent in DARPP-32 knockout mice. We propose that DARPP-32 mediated blunting of the response to ethanol subsequent to activation of ventral tegmental area dopaminergic neurons initiates molecular alterations that influence synaptic plasticity in this circuit, thereby promoting the development of ethanol reinforcement.</description><subject>2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine - pharmacology</subject><subject>Animal Genetics and Genomics</subject><subject>Animals</subject><subject>Behavioral Sciences</subject><subject>Biological Techniques</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Cell nuclei</subject><subject>Cyclic AMP - metabolism</subject><subject>Cyclic AMP-Dependent Protein Kinases - metabolism</subject><subject>Dopamine - metabolism</subject><subject>Dopamine Agonists - pharmacology</subject><subject>Dopamine and cAMP-Regulated Phosphoprotein 32</subject><subject>Ethanol - pharmacology</subject><subject>In Vitro Techniques</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Nerve Tissue Proteins</subject><subject>Neurobiology</subject><subject>Neuronal Plasticity - drug effects</subject><subject>Neuronal Plasticity - physiology</subject><subject>Neurosciences</subject><subject>Neurotransmitter receptors</subject><subject>Nucleus Accumbens - cytology</subject><subject>Nucleus Accumbens - drug effects</subject><subject>Nucleus Accumbens - metabolism</subject><subject>Phosphoproteins - deficiency</subject><subject>Phosphoproteins - genetics</subject><subject>Phosphoproteins - metabolism</subject><subject>Phosphorylation - drug effects</subject><subject>Physiological aspects</subject><subject>Rats</subject><subject>Receptors, Dopamine D1 - metabolism</subject><subject>Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors</subject><subject>Receptors, N-Methyl-D-Aspartate - drug effects</subject><subject>Receptors, N-Methyl-D-Aspartate - metabolism</subject><subject>Ventral Tegmental Area - physiology</subject><issn>1097-6256</issn><issn>1546-1726</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2002</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><recordid>eNqFkl1rFDEUhgex2A_7F2QQVLyYmu9kLpdWbaHVUvVShmzmzDZlJtnmQ9p_b7q7sKwXlVwk55znPTkvnKo6xugEI6o-OaekfFEdYM5EgyURL8sbtbIRhIv96jDGO4SQ5Kp9Ve1jgoSiiB9Uv89mN9fXDSW1dn0dYJFHnax3tR_qdAs1pFvt_FhHcNEm-8emx6fSt6uzWaENLJMPsbZuBbtsRsix1sbkaV4Ur6u9QY8Rjjf3UfXry-efp-fN5fevF6ezy8ZwSlMz9IoxZUivCREaD8DmUiCBMWhOGMYSGaZQiZDiXFPZM6NoW1KtpGB6To-qD-u-y-DvM8TUTTYaGEftwOfYKS6koFi1hXz_LCmx4qRtyX9BrJiQZYYCvv0HvPM5uGK3I5LJ4kiyAp2soYUeobNu8CloU04PkzXewWBLflY-5wKrleDjjqAwCR7SQucYu4sfN7vsuzVrgo8xwNAtg510eOww6p6Wo1stR-HebCbN8wn6LbXZhq3nWEpuAWFrZbfTXxU5vMU</recordid><startdate>20020701</startdate><enddate>20020701</enddate><creator>Maldve, R. 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E.</au><au>Zhang, T. A.</au><au>Ferrani-Kile, K.</au><au>Schreiber, S. S.</au><au>Lippmann, M. J.</au><au>Snyder, G. L.</au><au>Fienberg, A. A.</au><au>Leslie, S. W.</au><au>Gonzales, R. A.</au><au>Morrisett, R. A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>DARPP-32 and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens</atitle><jtitle>Nature neuroscience</jtitle><stitle>Nat Neurosci</stitle><addtitle>Nat Neurosci</addtitle><date>2002-07-01</date><risdate>2002</risdate><volume>5</volume><issue>7</issue><spage>641</spage><epage>648</epage><pages>641-648</pages><issn>1097-6256</issn><eissn>1546-1726</eissn><coden>NANEFN</coden><abstract>The medium spiny neurons of the nucleus accumbens receive both an excitatory glutamatergic input from forebrain and a dopaminergic input from the ventral tegmental area. This integration point may constitute a locus whereby the
N
-methyl-
D
-aspartate (NMDA)-subtype of glutamate receptors promotes drug reinforcement. Here we investigate how dopaminergic inputs alter the ethanol sensitivity of NMDA receptors in rats and mice and report that previous dopamine receptor-1 (D1) activation, culminating in dopamine and cAMP-regulated phosphoprotein-32 kD (DARPP-32) and NMDA receptor subunit-1 (NR1)-NMDA receptor phosphorylation, strongly decreases ethanol inhibition of NMDA responses. The regulation of ethanol sensitivity of NMDA receptors by D1 receptors was absent in DARPP-32 knockout mice. We propose that DARPP-32 mediated blunting of the response to ethanol subsequent to activation of ventral tegmental area dopaminergic neurons initiates molecular alterations that influence synaptic plasticity in this circuit, thereby promoting the development of ethanol reinforcement.</abstract><cop>New York</cop><pub>Nature Publishing Group US</pub><pmid>12068305</pmid><doi>10.1038/nn877</doi><tpages>8</tpages></addata></record> |
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| issn | 1097-6256 1546-1726 |
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| subjects | 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine - pharmacology Animal Genetics and Genomics Animals Behavioral Sciences Biological Techniques Biomedical and Life Sciences Biomedicine Cell nuclei Cyclic AMP - metabolism Cyclic AMP-Dependent Protein Kinases - metabolism Dopamine - metabolism Dopamine Agonists - pharmacology Dopamine and cAMP-Regulated Phosphoprotein 32 Ethanol - pharmacology In Vitro Techniques Mice Mice, Knockout Nerve Tissue Proteins Neurobiology Neuronal Plasticity - drug effects Neuronal Plasticity - physiology Neurosciences Neurotransmitter receptors Nucleus Accumbens - cytology Nucleus Accumbens - drug effects Nucleus Accumbens - metabolism Phosphoproteins - deficiency Phosphoproteins - genetics Phosphoproteins - metabolism Phosphorylation - drug effects Physiological aspects Rats Receptors, Dopamine D1 - metabolism Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors Receptors, N-Methyl-D-Aspartate - drug effects Receptors, N-Methyl-D-Aspartate - metabolism Ventral Tegmental Area - physiology |
| title | DARPP-32 and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens |
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