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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
Main Authors: 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.
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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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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. 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source ScienceDirect Freedom Collection
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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