Enhancing VTA Cav1.3 L-type Ca2+ channel activity promotes cocaine and mood-related behaviors via overlapping AMPA receptor mechanisms in the nucleus accumbens
Genetic factors significantly influence susceptibility for substance abuse and mood disorders. Rodent studies have begun to elucidate a role of Ca v 1.3 L-type Ca 2+ channels in neuropsychiatric-related behaviors, such as addictive and depressive-like behaviors. Human studies have also linked the CA...
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| Veröffentlicht in: | Molecular psychiatry 2017-12, Vol.22 (12), p.1735-1745 |
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| creator | Martínez-Rivera, A Hao, J Tropea, T F Giordano, T P Kosovsky, M Rice, R C Lee, A Huganir, R L Striessnig, J Addy, N A Han, S Rajadhyaksha, A M |
| description | Genetic factors significantly influence susceptibility for substance abuse and mood disorders. Rodent studies have begun to elucidate a role of Ca
v
1.3 L-type Ca
2+
channels in neuropsychiatric-related behaviors, such as addictive and depressive-like behaviors. Human studies have also linked the
CACNA1D
gene, which codes for the Ca
v
1.3 protein, with bipolar disorder. However, the neurocircuitry and the molecular mechanisms underlying the role of Ca
v
1.3 in neuropsychiatric phenotypes are not well established. In the present study, we directly manipulated Ca
v
1.3 channels in Ca
v
1.2 dihydropyridine insensitive mutant mice and found that ventral tegmental area (VTA) Ca
v
1.3 channels mediate cocaine-related and depressive-like behavior through a common nucleus accumbens (NAc) shell calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (CP-AMPAR) mechanism that requires GluA1 phosphorylation at S831. Selective activation of VTA Ca
v
1.3 with (±)-BayK-8644 (BayK) enhanced cocaine conditioned place preference and cocaine psychomotor activity while inducing depressive-like behavior, an effect not observed in S831A phospho-mutant mice. Infusion of the CP-AMPAR-specific blocker Naspm into the NAc shell reversed the cocaine and depressive-like phenotypes. In addition, activation of VTA Ca
v
1.3 channels resulted in social behavioral deficits. In contrast to the cocaine- and depression-related phenotypes, GluA1/A2 AMPARs in the NAc core mediated social deficits, independent of S831-GluA1 phosphorylation. Using a candidate gene analysis approach, we also identified single-nucleotide polymorphisms in the
CACNA1D
gene associated with cocaine dependence in human subjects. Together, our findings reveal novel, overlapping mechanisms through which VTA Ca
v
1.3 mediates cocaine-related, depressive-like and social phenotypes, suggesting that Ca
v
1.3 may serve as a target for the treatment of neuropsychiatric symptoms. |
| doi_str_mv | 10.1038/mp.2017.9 |
| format | Article |
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v
1.3 L-type Ca
2+
channels in neuropsychiatric-related behaviors, such as addictive and depressive-like behaviors. Human studies have also linked the
CACNA1D
gene, which codes for the Ca
v
1.3 protein, with bipolar disorder. However, the neurocircuitry and the molecular mechanisms underlying the role of Ca
v
1.3 in neuropsychiatric phenotypes are not well established. In the present study, we directly manipulated Ca
v
1.3 channels in Ca
v
1.2 dihydropyridine insensitive mutant mice and found that ventral tegmental area (VTA) Ca
v
1.3 channels mediate cocaine-related and depressive-like behavior through a common nucleus accumbens (NAc) shell calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (CP-AMPAR) mechanism that requires GluA1 phosphorylation at S831. Selective activation of VTA Ca
v
1.3 with (±)-BayK-8644 (BayK) enhanced cocaine conditioned place preference and cocaine psychomotor activity while inducing depressive-like behavior, an effect not observed in S831A phospho-mutant mice. Infusion of the CP-AMPAR-specific blocker Naspm into the NAc shell reversed the cocaine and depressive-like phenotypes. In addition, activation of VTA Ca
v
1.3 channels resulted in social behavioral deficits. In contrast to the cocaine- and depression-related phenotypes, GluA1/A2 AMPARs in the NAc core mediated social deficits, independent of S831-GluA1 phosphorylation. Using a candidate gene analysis approach, we also identified single-nucleotide polymorphisms in the
CACNA1D
gene associated with cocaine dependence in human subjects. Together, our findings reveal novel, overlapping mechanisms through which VTA Ca
v
1.3 mediates cocaine-related, depressive-like and social phenotypes, suggesting that Ca
v
1.3 may serve as a target for the treatment of neuropsychiatric symptoms.</description><identifier>ISSN: 1359-4184</identifier><identifier>ISSN: 1476-5578</identifier><identifier>EISSN: 1476-5578</identifier><identifier>DOI: 10.1038/mp.2017.9</identifier><identifier>PMID: 28194001</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/378 ; 692/699/476/1414 ; 692/699/476/5 ; Activation ; Analysis ; Behavior ; Behavioral Sciences ; Biological Psychology ; Bipolar disorder ; Calcium ; Calcium channels ; Calcium channels (L-type) ; Calcium channels (voltage-gated) ; Calcium permeability ; Care and treatment ; Caveolin-1 ; Channel gating ; Cocaine ; Conditioning ; Depression ; Depression (Mood disorder) ; Diagnosis ; Dihydropyridine ; Dosage and administration ; Drug abuse ; Genetic aspects ; Genetic factors ; Human behavior ; Medicine ; Medicine & Public Health ; Mental depression ; Mice ; Molecular modelling ; Mood ; Mutants ; Narcotics ; Neurosciences ; Nucleus accumbens ; original-article ; Pharmacotherapy ; Phenotypes ; Phosphorylation ; Place preference conditioning ; Psychiatry ; Receptor mechanisms ; Rodents ; Single nucleotide polymorphisms ; Single-nucleotide polymorphism ; Ventral tegmentum ; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid ; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors</subject><ispartof>Molecular psychiatry, 2017-12, Vol.22 (12), p.1735-1745</ispartof><rights>Macmillan Publishers Limited, part of Springer Nature. 2017</rights><rights>COPYRIGHT 2017 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Dec 2017</rights><rights>Macmillan Publishers Limited, part of Springer Nature. 2017.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4219-d6efab6621b7bff6e71d6538f795eb12d6a8f1c03def737446f423528e1b8d5c3</citedby><cites>FETCH-LOGICAL-c4219-d6efab6621b7bff6e71d6538f795eb12d6a8f1c03def737446f423528e1b8d5c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids></links><search><creatorcontrib>Martínez-Rivera, A</creatorcontrib><creatorcontrib>Hao, J</creatorcontrib><creatorcontrib>Tropea, T F</creatorcontrib><creatorcontrib>Giordano, T P</creatorcontrib><creatorcontrib>Kosovsky, M</creatorcontrib><creatorcontrib>Rice, R C</creatorcontrib><creatorcontrib>Lee, A</creatorcontrib><creatorcontrib>Huganir, R L</creatorcontrib><creatorcontrib>Striessnig, J</creatorcontrib><creatorcontrib>Addy, N A</creatorcontrib><creatorcontrib>Han, S</creatorcontrib><creatorcontrib>Rajadhyaksha, A M</creatorcontrib><title>Enhancing VTA Cav1.3 L-type Ca2+ channel activity promotes cocaine and mood-related behaviors via overlapping AMPA receptor mechanisms in the nucleus accumbens</title><title>Molecular psychiatry</title><addtitle>Mol Psychiatry</addtitle><description>Genetic factors significantly influence susceptibility for substance abuse and mood disorders. Rodent studies have begun to elucidate a role of Ca
v
1.3 L-type Ca
2+
channels in neuropsychiatric-related behaviors, such as addictive and depressive-like behaviors. Human studies have also linked the
CACNA1D
gene, which codes for the Ca
v
1.3 protein, with bipolar disorder. However, the neurocircuitry and the molecular mechanisms underlying the role of Ca
v
1.3 in neuropsychiatric phenotypes are not well established. In the present study, we directly manipulated Ca
v
1.3 channels in Ca
v
1.2 dihydropyridine insensitive mutant mice and found that ventral tegmental area (VTA) Ca
v
1.3 channels mediate cocaine-related and depressive-like behavior through a common nucleus accumbens (NAc) shell calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (CP-AMPAR) mechanism that requires GluA1 phosphorylation at S831. Selective activation of VTA Ca
v
1.3 with (±)-BayK-8644 (BayK) enhanced cocaine conditioned place preference and cocaine psychomotor activity while inducing depressive-like behavior, an effect not observed in S831A phospho-mutant mice. Infusion of the CP-AMPAR-specific blocker Naspm into the NAc shell reversed the cocaine and depressive-like phenotypes. In addition, activation of VTA Ca
v
1.3 channels resulted in social behavioral deficits. In contrast to the cocaine- and depression-related phenotypes, GluA1/A2 AMPARs in the NAc core mediated social deficits, independent of S831-GluA1 phosphorylation. Using a candidate gene analysis approach, we also identified single-nucleotide polymorphisms in the
CACNA1D
gene associated with cocaine dependence in human subjects. Together, our findings reveal novel, overlapping mechanisms through which VTA Ca
v
1.3 mediates cocaine-related, depressive-like and social phenotypes, suggesting that Ca
v
1.3 may serve as a target for the treatment of neuropsychiatric symptoms.</description><subject>631/378</subject><subject>692/699/476/1414</subject><subject>692/699/476/5</subject><subject>Activation</subject><subject>Analysis</subject><subject>Behavior</subject><subject>Behavioral Sciences</subject><subject>Biological Psychology</subject><subject>Bipolar disorder</subject><subject>Calcium</subject><subject>Calcium channels</subject><subject>Calcium channels (L-type)</subject><subject>Calcium channels (voltage-gated)</subject><subject>Calcium permeability</subject><subject>Care and treatment</subject><subject>Caveolin-1</subject><subject>Channel gating</subject><subject>Cocaine</subject><subject>Conditioning</subject><subject>Depression</subject><subject>Depression (Mood disorder)</subject><subject>Diagnosis</subject><subject>Dihydropyridine</subject><subject>Dosage and administration</subject><subject>Drug abuse</subject><subject>Genetic aspects</subject><subject>Genetic factors</subject><subject>Human behavior</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mental depression</subject><subject>Mice</subject><subject>Molecular modelling</subject><subject>Mood</subject><subject>Mutants</subject><subject>Narcotics</subject><subject>Neurosciences</subject><subject>Nucleus accumbens</subject><subject>original-article</subject><subject>Pharmacotherapy</subject><subject>Phenotypes</subject><subject>Phosphorylation</subject><subject>Place preference conditioning</subject><subject>Psychiatry</subject><subject>Receptor mechanisms</subject><subject>Rodents</subject><subject>Single nucleotide polymorphisms</subject><subject>Single-nucleotide polymorphism</subject><subject>Ventral tegmentum</subject><subject>α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid</subject><subject>α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors</subject><issn>1359-4184</issn><issn>1476-5578</issn><issn>1476-5578</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><recordid>eNp9kt2O1SAQxxujcT_0wjcg8UbX9FhKofTGpDlZP5Jj9GL1llA6nMOmQIW2yXkaX1Was1FXjXABw_zmPzNksuwZLja4IPy1HTdlgetN8yA7x1XNckpr_jDdCW3yCvPqLLuI8bYoVid9nJ2VHDdVMs-z79fuIJ0ybo--3rRoKxe8IWiXT8cRklW-Qir5HQxIqsksZjqiMXjrJ4hIeSWNAyRdj6z3fR5gkBP0qIODXIwPES1GIr9AGOQ4rjnaj59bFEDBOPmALKziJtqIjEPTAZCb1QBzTMnUbDtw8Un2SMshwtO78zL78vb6Zvs-331692Hb7nJVlbjJewZadoyVuKs7rRnUuGeUcF03FDpc9kxyjVVBetA1qauK6aoktOSAO95TRS6zNyfdce4s9ArcFOQgxmCsDEfhpRH3Pc4cxN4vgqbFSZ0EXtwJBP9thjgJa6KCYZAO_BwF5oyThvOiSejzP9BbPweX2hMlw5QSTDn9H4UbxmnVYFz9ovZyAGGc9qk6taYWLU06mJJ6LW7zDyrtHqxR3oE26f1ewMtTgAo-xgD650_gQqwzJ-wo1pkTaztXJzYmxu0h_FboX_APcePVqg</recordid><startdate>20171201</startdate><enddate>20171201</enddate><creator>Martínez-Rivera, 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accumbens</title><author>Martínez-Rivera, A ; Hao, J ; Tropea, T F ; Giordano, T P ; Kosovsky, M ; Rice, R C ; Lee, A ; Huganir, R L ; Striessnig, J ; Addy, N A ; Han, S ; Rajadhyaksha, A M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4219-d6efab6621b7bff6e71d6538f795eb12d6a8f1c03def737446f423528e1b8d5c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>631/378</topic><topic>692/699/476/1414</topic><topic>692/699/476/5</topic><topic>Activation</topic><topic>Analysis</topic><topic>Behavior</topic><topic>Behavioral Sciences</topic><topic>Biological Psychology</topic><topic>Bipolar disorder</topic><topic>Calcium</topic><topic>Calcium channels</topic><topic>Calcium channels (L-type)</topic><topic>Calcium channels (voltage-gated)</topic><topic>Calcium permeability</topic><topic>Care and treatment</topic><topic>Caveolin-1</topic><topic>Channel gating</topic><topic>Cocaine</topic><topic>Conditioning</topic><topic>Depression</topic><topic>Depression (Mood disorder)</topic><topic>Diagnosis</topic><topic>Dihydropyridine</topic><topic>Dosage and administration</topic><topic>Drug abuse</topic><topic>Genetic aspects</topic><topic>Genetic factors</topic><topic>Human behavior</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mental depression</topic><topic>Mice</topic><topic>Molecular modelling</topic><topic>Mood</topic><topic>Mutants</topic><topic>Narcotics</topic><topic>Neurosciences</topic><topic>Nucleus accumbens</topic><topic>original-article</topic><topic>Pharmacotherapy</topic><topic>Phenotypes</topic><topic>Phosphorylation</topic><topic>Place preference conditioning</topic><topic>Psychiatry</topic><topic>Receptor mechanisms</topic><topic>Rodents</topic><topic>Single nucleotide polymorphisms</topic><topic>Single-nucleotide polymorphism</topic><topic>Ventral tegmentum</topic><topic>α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid</topic><topic>α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Martínez-Rivera, A</creatorcontrib><creatorcontrib>Hao, J</creatorcontrib><creatorcontrib>Tropea, T F</creatorcontrib><creatorcontrib>Giordano, T P</creatorcontrib><creatorcontrib>Kosovsky, M</creatorcontrib><creatorcontrib>Rice, R C</creatorcontrib><creatorcontrib>Lee, A</creatorcontrib><creatorcontrib>Huganir, R L</creatorcontrib><creatorcontrib>Striessnig, J</creatorcontrib><creatorcontrib>Addy, N A</creatorcontrib><creatorcontrib>Han, S</creatorcontrib><creatorcontrib>Rajadhyaksha, A M</creatorcontrib><collection>CrossRef</collection><collection>ProQuest Central (Corporate)</collection><collection>Neurosciences Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 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Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Martínez-Rivera, A</au><au>Hao, J</au><au>Tropea, T F</au><au>Giordano, T P</au><au>Kosovsky, M</au><au>Rice, R C</au><au>Lee, A</au><au>Huganir, R L</au><au>Striessnig, J</au><au>Addy, N A</au><au>Han, S</au><au>Rajadhyaksha, A M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Enhancing VTA Cav1.3 L-type Ca2+ channel activity promotes cocaine and mood-related behaviors via overlapping AMPA receptor mechanisms in the nucleus accumbens</atitle><jtitle>Molecular psychiatry</jtitle><stitle>Mol Psychiatry</stitle><date>2017-12-01</date><risdate>2017</risdate><volume>22</volume><issue>12</issue><spage>1735</spage><epage>1745</epage><pages>1735-1745</pages><issn>1359-4184</issn><issn>1476-5578</issn><eissn>1476-5578</eissn><abstract>Genetic factors significantly influence susceptibility for substance abuse and mood disorders. Rodent studies have begun to elucidate a role of Ca
v
1.3 L-type Ca
2+
channels in neuropsychiatric-related behaviors, such as addictive and depressive-like behaviors. Human studies have also linked the
CACNA1D
gene, which codes for the Ca
v
1.3 protein, with bipolar disorder. However, the neurocircuitry and the molecular mechanisms underlying the role of Ca
v
1.3 in neuropsychiatric phenotypes are not well established. In the present study, we directly manipulated Ca
v
1.3 channels in Ca
v
1.2 dihydropyridine insensitive mutant mice and found that ventral tegmental area (VTA) Ca
v
1.3 channels mediate cocaine-related and depressive-like behavior through a common nucleus accumbens (NAc) shell calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (CP-AMPAR) mechanism that requires GluA1 phosphorylation at S831. Selective activation of VTA Ca
v
1.3 with (±)-BayK-8644 (BayK) enhanced cocaine conditioned place preference and cocaine psychomotor activity while inducing depressive-like behavior, an effect not observed in S831A phospho-mutant mice. Infusion of the CP-AMPAR-specific blocker Naspm into the NAc shell reversed the cocaine and depressive-like phenotypes. In addition, activation of VTA Ca
v
1.3 channels resulted in social behavioral deficits. In contrast to the cocaine- and depression-related phenotypes, GluA1/A2 AMPARs in the NAc core mediated social deficits, independent of S831-GluA1 phosphorylation. Using a candidate gene analysis approach, we also identified single-nucleotide polymorphisms in the
CACNA1D
gene associated with cocaine dependence in human subjects. Together, our findings reveal novel, overlapping mechanisms through which VTA Ca
v
1.3 mediates cocaine-related, depressive-like and social phenotypes, suggesting that Ca
v
1.3 may serve as a target for the treatment of neuropsychiatric symptoms.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>28194001</pmid><doi>10.1038/mp.2017.9</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1359-4184 |
| ispartof | Molecular psychiatry, 2017-12, Vol.22 (12), p.1735-1745 |
| issn | 1359-4184 1476-5578 1476-5578 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5555837 |
| source | Alma/SFX Local Collection |
| subjects | 631/378 692/699/476/1414 692/699/476/5 Activation Analysis Behavior Behavioral Sciences Biological Psychology Bipolar disorder Calcium Calcium channels Calcium channels (L-type) Calcium channels (voltage-gated) Calcium permeability Care and treatment Caveolin-1 Channel gating Cocaine Conditioning Depression Depression (Mood disorder) Diagnosis Dihydropyridine Dosage and administration Drug abuse Genetic aspects Genetic factors Human behavior Medicine Medicine & Public Health Mental depression Mice Molecular modelling Mood Mutants Narcotics Neurosciences Nucleus accumbens original-article Pharmacotherapy Phenotypes Phosphorylation Place preference conditioning Psychiatry Receptor mechanisms Rodents Single nucleotide polymorphisms Single-nucleotide polymorphism Ventral tegmentum α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors |
| title | Enhancing VTA Cav1.3 L-type Ca2+ channel activity promotes cocaine and mood-related behaviors via overlapping AMPA receptor mechanisms in the nucleus accumbens |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-28T16%3A22%3A20IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Enhancing%20VTA%20Cav1.3%20L-type%20Ca2+%20channel%20activity%20promotes%20cocaine%20and%20mood-related%20behaviors%20via%20overlapping%20AMPA%20receptor%20mechanisms%20in%20the%20nucleus%20accumbens&rft.jtitle=Molecular%20psychiatry&rft.au=Mart%C3%ADnez-Rivera,%20A&rft.date=2017-12-01&rft.volume=22&rft.issue=12&rft.spage=1735&rft.epage=1745&rft.pages=1735-1745&rft.issn=1359-4184&rft.eissn=1476-5578&rft_id=info:doi/10.1038/mp.2017.9&rft_dat=%3Cgale_pubme%3EA515815377%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1968549114&rft_id=info:pmid/28194001&rft_galeid=A515815377&rfr_iscdi=true |