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Research ArticleNEUROPHARMACOLOGY

Persistent Antagonism of Methamphetamine-Induced Dopamine Release in Rats Pretreated with GBR12909 Decanoate

Michael H. Baumann, Mario A. Ayestas, Lawrence G. Sharpe, David B. Lewis, Kenner C. Rice and Richard B. Rothman
Journal of Pharmacology and Experimental Therapeutics June 2002, 301 (3) 1190-1197; DOI: https://doi.org/10.1124/jpet.301.3.1190
Michael H. Baumann
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Mario A. Ayestas
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Lawrence G. Sharpe
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David B. Lewis
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Kenner C. Rice
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Richard B. Rothman
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Abstract

Methamphetamine abuse is a serious global health problem, and no effective treatments for methamphetamine dependence have been developed. In animals, the addictive properties of methamphetamine are mediated via release of dopamine (DA) from nerve terminals in mesolimbic reward circuits. At the molecular level, methamphetamine promotes DA release by a nonexocytotic diffusion-exchange process involving DA transporter (DAT) proteins. We have shown that blocking DAT activity with high-affinity DA uptake inhibitors, such as 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl) piperazine (GBR12909), can substantially reduce amphetamine-induced DA release in vivo. In the present study, we examined the ability of a long-acting depot formulation of GBR12909 decanoate (GBR-decanoate) to influence neurochemical actions of methamphetamine in the nucleus accumbens of rats. Rats received single injections of GBR-decanoate (480 mg/kg i.m.) and were subjected to in vivo microdialysis testing 1 and 2 weeks later. Pretreatment with GBR-decanoate produced modest elevations in basal extracellular levels of DA, but not 5-hydroxytryptamine (5-HT), at both time points. GBR-decanoate nearly eliminated the DA-releasing ability of methamphetamine (0.3 and 1.0 mg/kg i.v.) for 2 weeks, whereas methamphetamine-induced 5-HT release was unaffected. Autoradiographic analysis revealed that GBR-decanoate caused long-term decreases in DAT binding in the brain. Our data suggest that GBR-decanoate, or similar agents, may be useful adjuncts in treating methamphetamine dependence. This therapeutic strategy would be especially useful for noncompliant patient populations.

Footnotes

  • This work was generously supported by the Intramural Research Program of the National Institute on Drug Abuse.

  • Abbreviations:
    DA
    dopamine
    DAT
    dopamine transporter
    GBR12909
    1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl) piperazine
    GBR-decanoate
    GBR12909 decanoate
    GBR-hydroxy
    1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-hydroxy-3-phenylpropyl) piperazine
    RTI-55
    3β-(4-iodophenyl)tropan-2β-carboxylic acid methyl ester
    5-HT
    serotonin
    SERT
    5-hydroxytryptamine transporter
    HPLC
    high-pressure liquid chromatography
    METH
    methamphetamine
    • Received November 13, 2001.
    • Accepted February 27, 2002.
  • U.S. Government
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Journal of Pharmacology and Experimental Therapeutics: 301 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 3
1 Jun 2002
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Research ArticleNEUROPHARMACOLOGY

Persistent Antagonism of Methamphetamine-Induced Dopamine Release in Rats Pretreated with GBR12909 Decanoate

Michael H. Baumann, Mario A. Ayestas, Lawrence G. Sharpe, David B. Lewis, Kenner C. Rice and Richard B. Rothman
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 1190-1197; DOI: https://doi.org/10.1124/jpet.301.3.1190

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Research ArticleNEUROPHARMACOLOGY

Persistent Antagonism of Methamphetamine-Induced Dopamine Release in Rats Pretreated with GBR12909 Decanoate

Michael H. Baumann, Mario A. Ayestas, Lawrence G. Sharpe, David B. Lewis, Kenner C. Rice and Richard B. Rothman
Journal of Pharmacology and Experimental Therapeutics June 1, 2002, 301 (3) 1190-1197; DOI: https://doi.org/10.1124/jpet.301.3.1190
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