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Tight binding dopamine reuptake inhibitors as cocaine antagonists
Author(s) -
Rothman Richard B.,
Mele Andrea,
Reid Audrey A.,
Akunne Hyacinth,
Greig Nigel,
Thurkauf Andrew,
Rice Kenner C.,
Pert Agu
Publication year - 1989
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(89)81566-2
Subject(s) - reuptake , microdialysis , chemistry , pharmacology , reuptake inhibitor , dopamine transporter , dopamine , antagonist , dopamine uptake inhibitors , dopamine plasma membrane transport proteins , norepinephrine transporter , tropane , transporter , extracellular , medicine , biochemistry , stereochemistry , serotonin , receptor , gene , nucleus accumbens
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 [ 3 H]cocaine or [ 3 H]1‐[2‐(diphenyl‐methoxy)ethyl]‐4‐(3‐phenylpropyl)piperazine ([ 3 H]GBR12935), indicative of tight binding. In vivo microdialysis experiments showed that administration of 25GBR12909 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.