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Atypical dopamine transporter inhibitors attenuate compulsive-like methamphetamine self-administration in rats
Methamphetamine (METH) is a highly addictive drug, but no pharmacological treatment is yet available for METH use disorders. Similar to METH, the wake-promoting drug (R)-modafinil (R-MOD) binds to the dopamine transporter (DAT). Unlike METH, R-MOD is not a substrate for transport by DAT and has low...
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Published in: | Neuropharmacology 2018-03, Vol.131, p.96-103 |
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creator | Tunstall, Brendan J. Ho, Chelsea P. Cao, Jianjing Vendruscolo, Janaína C.M. Schmeichel, Brooke E. Slack, Rachel D. Tanda, Gianluigi Gadiano, Alexandra J. Rais, Rana Slusher, Barbara S. Koob, George F. Newman, Amy H. Vendruscolo, Leandro F. |
description | Methamphetamine (METH) is a highly addictive drug, but no pharmacological treatment is yet available for METH use disorders. Similar to METH, the wake-promoting drug (R)-modafinil (R-MOD) binds to the dopamine transporter (DAT). Unlike METH, R-MOD is not a substrate for transport by DAT and has low abuse potential. We tested the hypothesis that the atypical DAT inhibitor R-MOD and compounds that are derived from modafinil would decrease METH intake by reducing the actions of METH at the DAT. We tested the effects of systemic injections of R-MOD and four novel modafinil-derived ligands with increased DAT affinity (JJC8-016, JJC8-088, JJC8-089, and JJC8-091) on intravenous (i.v.) METH self-administration in rats that were allowed short access (ShA; 1 h) or long access (LgA; 6 h) to the drug. ShA rats exhibited stable METH intake over sessions, whereas LgA rats exhibited an escalation of drug intake. R-MOD decreased METH self-administration in ShA and LgA rats (in the 1st hour only). JJC8-091 and JJC8-016 decreased METH self-administration in both ShA and LgA rats. JJC8-089 decreased METH self-administration in LgA rats only, whereas JJC8-088 had no effect on METH self-administration in either ShA or LgA rats. These findings support the potential of atypical DAT inhibitors for the treatment of METH use disorders and suggest several novel compounds as candidate drugs.
•There is currently no available pharmacological treatment for METH use disorder.•Rats allowed extended access to METH escalate their drug intake.•R-Modafinil and several modafinil analogues reduced escalated METH intake.•Atypical DAT inhibitors have potential for treating METH use disorders. |
doi_str_mv | 10.1016/j.neuropharm.2017.12.006 |
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•There is currently no available pharmacological treatment for METH use disorder.•Rats allowed extended access to METH escalate their drug intake.•R-Modafinil and several modafinil analogues reduced escalated METH intake.•Atypical DAT inhibitors have potential for treating METH use disorders.</description><identifier>ISSN: 0028-3908</identifier><identifier>EISSN: 1873-7064</identifier><identifier>DOI: 10.1016/j.neuropharm.2017.12.006</identifier><identifier>PMID: 29217282</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Addiction ; Analysis of Variance ; Animals ; Benzhydryl Compounds - therapeutic use ; Central Nervous System Stimulants - administration & dosage ; Compulsive Behavior - drug therapy ; Conditioning, Operant - drug effects ; Dopamine Antagonists - pharmacokinetics ; Dopamine Antagonists - therapeutic use ; Dopamine Plasma Membrane Transport Proteins - antagonists & inhibitors ; Dopamine Plasma Membrane Transport Proteins - metabolism ; Dopamine transporter (DAT) ; Dose-Response Relationship, Drug ; Drug dependence ; Male ; Methamphetamine ; Methamphetamine - administration & dosage ; Modafinil ; Operant intravenous self-administration ; Propylamines - pharmacokinetics ; Propylamines - therapeutic use ; Rats ; Rats, Wistar ; Saccharin - administration & dosage ; Self Administration ; Time Factors ; Wakefulness-Promoting Agents</subject><ispartof>Neuropharmacology, 2018-03, Vol.131, p.96-103</ispartof><rights>2017</rights><rights>Published by Elsevier Ltd.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c479t-c2cc62691b1117a45a5647c16fb5ae5ab261402ae04692546a84ac1213865ed73</citedby><cites>FETCH-LOGICAL-c479t-c2cc62691b1117a45a5647c16fb5ae5ab261402ae04692546a84ac1213865ed73</cites><orcidid>0000-0001-9430-9612</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29217282$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Tunstall, Brendan J.</creatorcontrib><creatorcontrib>Ho, Chelsea P.</creatorcontrib><creatorcontrib>Cao, Jianjing</creatorcontrib><creatorcontrib>Vendruscolo, Janaína C.M.</creatorcontrib><creatorcontrib>Schmeichel, Brooke E.</creatorcontrib><creatorcontrib>Slack, Rachel D.</creatorcontrib><creatorcontrib>Tanda, Gianluigi</creatorcontrib><creatorcontrib>Gadiano, Alexandra J.</creatorcontrib><creatorcontrib>Rais, Rana</creatorcontrib><creatorcontrib>Slusher, Barbara S.</creatorcontrib><creatorcontrib>Koob, George F.</creatorcontrib><creatorcontrib>Newman, Amy H.</creatorcontrib><creatorcontrib>Vendruscolo, Leandro F.</creatorcontrib><title>Atypical dopamine transporter inhibitors attenuate compulsive-like methamphetamine self-administration in rats</title><title>Neuropharmacology</title><addtitle>Neuropharmacology</addtitle><description>Methamphetamine (METH) is a highly addictive drug, but no pharmacological treatment is yet available for METH use disorders. Similar to METH, the wake-promoting drug (R)-modafinil (R-MOD) binds to the dopamine transporter (DAT). Unlike METH, R-MOD is not a substrate for transport by DAT and has low abuse potential. We tested the hypothesis that the atypical DAT inhibitor R-MOD and compounds that are derived from modafinil would decrease METH intake by reducing the actions of METH at the DAT. We tested the effects of systemic injections of R-MOD and four novel modafinil-derived ligands with increased DAT affinity (JJC8-016, JJC8-088, JJC8-089, and JJC8-091) on intravenous (i.v.) METH self-administration in rats that were allowed short access (ShA; 1 h) or long access (LgA; 6 h) to the drug. ShA rats exhibited stable METH intake over sessions, whereas LgA rats exhibited an escalation of drug intake. R-MOD decreased METH self-administration in ShA and LgA rats (in the 1st hour only). JJC8-091 and JJC8-016 decreased METH self-administration in both ShA and LgA rats. JJC8-089 decreased METH self-administration in LgA rats only, whereas JJC8-088 had no effect on METH self-administration in either ShA or LgA rats. These findings support the potential of atypical DAT inhibitors for the treatment of METH use disorders and suggest several novel compounds as candidate drugs.
•There is currently no available pharmacological treatment for METH use disorder.•Rats allowed extended access to METH escalate their drug intake.•R-Modafinil and several modafinil analogues reduced escalated METH intake.•Atypical DAT inhibitors have potential for treating METH use disorders.</description><subject>Addiction</subject><subject>Analysis of Variance</subject><subject>Animals</subject><subject>Benzhydryl Compounds - therapeutic use</subject><subject>Central Nervous System Stimulants - administration & dosage</subject><subject>Compulsive Behavior - drug therapy</subject><subject>Conditioning, Operant - drug effects</subject><subject>Dopamine Antagonists - pharmacokinetics</subject><subject>Dopamine Antagonists - therapeutic use</subject><subject>Dopamine Plasma Membrane Transport Proteins - antagonists & inhibitors</subject><subject>Dopamine Plasma Membrane Transport Proteins - metabolism</subject><subject>Dopamine transporter (DAT)</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug dependence</subject><subject>Male</subject><subject>Methamphetamine</subject><subject>Methamphetamine - administration & dosage</subject><subject>Modafinil</subject><subject>Operant intravenous self-administration</subject><subject>Propylamines - pharmacokinetics</subject><subject>Propylamines - therapeutic use</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Saccharin - administration & dosage</subject><subject>Self Administration</subject><subject>Time Factors</subject><subject>Wakefulness-Promoting Agents</subject><issn>0028-3908</issn><issn>1873-7064</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNqFkU1v1DAQhi1ERZeWv4By5JLgcRLHuSCVqnxIlbi0Z2vizBIviR1sZ6X-e1xtKXDi5JH8zjOjeRgrgFfAQb4_VI624NcJw1IJDl0FouJcvmA7UF1ddlw2L9mOc6HKuufqnL2O8cA5bxSoV-xc9AI6ocSOuav0sFqDczH6FRfrqEgBXVx9SBQK6yY72ORDLDAlchsmKoxf1m2O9kjlbH9QsVCacFknSidApHlf4phrGzMsWe8yqMhVvGRne5wjvXl6L9j9p5u76y_l7bfPX6-vbkvTdH0qjTBGCtnDAAAdNi22sukMyP3QIrU4CAkNF0i8kb1oG4mqQQMCaiVbGrv6gn04cddtWGg05PIis16DXTA8aI9W__vj7KS_-6NuVT4n1Bnw7gkQ_M-NYtKLjYbmGR35LWrou5ZDK3mfo-oUNcHHGGj_PAa4ftSlD_qPLv2oS4PQWVduffv3ms-Nv_3kwMdTgPKxjpaCjsaSMzTaQCbp0dv_T_kFlsiwKA</recordid><startdate>20180315</startdate><enddate>20180315</enddate><creator>Tunstall, Brendan J.</creator><creator>Ho, Chelsea P.</creator><creator>Cao, Jianjing</creator><creator>Vendruscolo, Janaína C.M.</creator><creator>Schmeichel, Brooke E.</creator><creator>Slack, Rachel D.</creator><creator>Tanda, Gianluigi</creator><creator>Gadiano, Alexandra J.</creator><creator>Rais, Rana</creator><creator>Slusher, Barbara S.</creator><creator>Koob, George F.</creator><creator>Newman, Amy H.</creator><creator>Vendruscolo, Leandro F.</creator><general>Elsevier Ltd</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>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9430-9612</orcidid></search><sort><creationdate>20180315</creationdate><title>Atypical dopamine transporter inhibitors attenuate compulsive-like methamphetamine self-administration in rats</title><author>Tunstall, Brendan J. ; Ho, Chelsea P. ; Cao, Jianjing ; Vendruscolo, Janaína C.M. ; Schmeichel, Brooke E. ; Slack, Rachel D. ; Tanda, Gianluigi ; Gadiano, Alexandra J. ; Rais, Rana ; Slusher, Barbara S. ; Koob, George F. ; Newman, Amy H. ; Vendruscolo, Leandro F.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c479t-c2cc62691b1117a45a5647c16fb5ae5ab261402ae04692546a84ac1213865ed73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Addiction</topic><topic>Analysis of Variance</topic><topic>Animals</topic><topic>Benzhydryl Compounds - therapeutic use</topic><topic>Central Nervous System Stimulants - administration & dosage</topic><topic>Compulsive Behavior - drug therapy</topic><topic>Conditioning, Operant - drug effects</topic><topic>Dopamine Antagonists - pharmacokinetics</topic><topic>Dopamine Antagonists - therapeutic use</topic><topic>Dopamine Plasma Membrane Transport Proteins - antagonists & inhibitors</topic><topic>Dopamine Plasma Membrane Transport Proteins - metabolism</topic><topic>Dopamine transporter (DAT)</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug dependence</topic><topic>Male</topic><topic>Methamphetamine</topic><topic>Methamphetamine - administration & dosage</topic><topic>Modafinil</topic><topic>Operant intravenous self-administration</topic><topic>Propylamines - pharmacokinetics</topic><topic>Propylamines - therapeutic use</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Saccharin - administration & dosage</topic><topic>Self Administration</topic><topic>Time Factors</topic><topic>Wakefulness-Promoting Agents</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Tunstall, Brendan J.</creatorcontrib><creatorcontrib>Ho, Chelsea P.</creatorcontrib><creatorcontrib>Cao, Jianjing</creatorcontrib><creatorcontrib>Vendruscolo, Janaína C.M.</creatorcontrib><creatorcontrib>Schmeichel, Brooke E.</creatorcontrib><creatorcontrib>Slack, Rachel D.</creatorcontrib><creatorcontrib>Tanda, Gianluigi</creatorcontrib><creatorcontrib>Gadiano, Alexandra J.</creatorcontrib><creatorcontrib>Rais, Rana</creatorcontrib><creatorcontrib>Slusher, Barbara S.</creatorcontrib><creatorcontrib>Koob, George F.</creatorcontrib><creatorcontrib>Newman, Amy H.</creatorcontrib><creatorcontrib>Vendruscolo, Leandro F.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Neuropharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Tunstall, Brendan J.</au><au>Ho, Chelsea P.</au><au>Cao, Jianjing</au><au>Vendruscolo, Janaína C.M.</au><au>Schmeichel, Brooke E.</au><au>Slack, Rachel D.</au><au>Tanda, Gianluigi</au><au>Gadiano, Alexandra J.</au><au>Rais, Rana</au><au>Slusher, Barbara S.</au><au>Koob, George F.</au><au>Newman, Amy H.</au><au>Vendruscolo, Leandro F.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Atypical dopamine transporter inhibitors attenuate compulsive-like methamphetamine self-administration in rats</atitle><jtitle>Neuropharmacology</jtitle><addtitle>Neuropharmacology</addtitle><date>2018-03-15</date><risdate>2018</risdate><volume>131</volume><spage>96</spage><epage>103</epage><pages>96-103</pages><issn>0028-3908</issn><eissn>1873-7064</eissn><abstract>Methamphetamine (METH) is a highly addictive drug, but no pharmacological treatment is yet available for METH use disorders. Similar to METH, the wake-promoting drug (R)-modafinil (R-MOD) binds to the dopamine transporter (DAT). Unlike METH, R-MOD is not a substrate for transport by DAT and has low abuse potential. We tested the hypothesis that the atypical DAT inhibitor R-MOD and compounds that are derived from modafinil would decrease METH intake by reducing the actions of METH at the DAT. We tested the effects of systemic injections of R-MOD and four novel modafinil-derived ligands with increased DAT affinity (JJC8-016, JJC8-088, JJC8-089, and JJC8-091) on intravenous (i.v.) METH self-administration in rats that were allowed short access (ShA; 1 h) or long access (LgA; 6 h) to the drug. ShA rats exhibited stable METH intake over sessions, whereas LgA rats exhibited an escalation of drug intake. R-MOD decreased METH self-administration in ShA and LgA rats (in the 1st hour only). JJC8-091 and JJC8-016 decreased METH self-administration in both ShA and LgA rats. JJC8-089 decreased METH self-administration in LgA rats only, whereas JJC8-088 had no effect on METH self-administration in either ShA or LgA rats. These findings support the potential of atypical DAT inhibitors for the treatment of METH use disorders and suggest several novel compounds as candidate drugs.
•There is currently no available pharmacological treatment for METH use disorder.•Rats allowed extended access to METH escalate their drug intake.•R-Modafinil and several modafinil analogues reduced escalated METH intake.•Atypical DAT inhibitors have potential for treating METH use disorders.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>29217282</pmid><doi>10.1016/j.neuropharm.2017.12.006</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0001-9430-9612</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Addiction Analysis of Variance Animals Benzhydryl Compounds - therapeutic use Central Nervous System Stimulants - administration & dosage Compulsive Behavior - drug therapy Conditioning, Operant - drug effects Dopamine Antagonists - pharmacokinetics Dopamine Antagonists - therapeutic use Dopamine Plasma Membrane Transport Proteins - antagonists & inhibitors Dopamine Plasma Membrane Transport Proteins - metabolism Dopamine transporter (DAT) Dose-Response Relationship, Drug Drug dependence Male Methamphetamine Methamphetamine - administration & dosage Modafinil Operant intravenous self-administration Propylamines - pharmacokinetics Propylamines - therapeutic use Rats Rats, Wistar Saccharin - administration & dosage Self Administration Time Factors Wakefulness-Promoting Agents |
title | Atypical dopamine transporter inhibitors attenuate compulsive-like methamphetamine self-administration in rats |
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