Tight binding dopamine reuptake inhibitors as cocaine antagonists

FEBS Letters

Rice, Kenner C.³  Mele, Andrea⁴  Pert, Agu⁴  Reid, Audrey A.³  Akunne, Hyacinth¹  Rothman, Richard B.¹  Greig, Nigel²  Thurkauf, Andrew³ 

[1] Unit on Receptor Studies, LCS, NIMH, Bldg 10-3D41, Bethesda, MD 20892 USA;Laboratory of Neurosciences, NIA, Bethesda, MD 20892, USA;Laboratory of Medicinal Chemistry, NIDDK, Bethesda, MD 20892 USA;Biological Psychiatry Branch, NIMH, Bethesda, MD 20892 USA

关键词: Cocaine;    Dopamine reuptake inhibitor;    Microdialysis;    in vivo;    Dopamine;    GBR12909;    1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine;    GBR12935;    1-[2-(diphenyl-methoxy)-ethyl]-4-(3-phenylpropyl)piperazine;    DA;    dopamine;    ECDA;    extracellular dopamine;    aCSF;    artificial CSF;   

DOI  :  10.1016/0014-5793(89)81566-2

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

The experiments reported in this study tested the hypothesis that tight binding dopamine (DA) reuptake inhibitors might act as cocaine antagonists. Binding studies demonstrated that the high affinity dopamine reuptake inhibitor, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3-phenylpropyl]piperazine (GBR12909) produced a wash-resistant inhibition of the DA transporter in rat striatal membranes as labeled by [³H]cocaine or [³H]1-[2-(diphenyl-methoxy)ethyl]-4-(3-phenylpropyl)piperazine ([³H]GBR12935), indicative of tight binding. In vivo microdialysis experiments showed that administration of 25 GBR12909 to rats produced a modest, but not statistically significant, increase in the extracellular levels of striatal DA, while this same dose of GBR12909 inhibited the ability of cocaine to elevate extracellular DA levels by 64%. These data suggest that tight binding DA reuptake blockers may provide a fruitful approach for developing a cocaine antagonist.

【 授权许可】

Unknown