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Studies of the biogenic amine transporters. VII. Characterization of a novel cocaine binding site identified with [ 125 I]RTI‐55 in membranes prepared from human, monkey and guinea pig caudate
Author(s) -
Rothman Richard B.,
Silverthorn Mayme L.,
Glowa John R.,
Matecka Dorota,
Rice Kenner C.,
Carroll F. Ivy,
Partilla John S.,
Uhl George R.,
Vandenbergh David J.,
Dersch Christina M.
Publication year - 1998
Publication title -
synapse
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.809
H-Index - 106
eISSN - 1098-2396
pISSN - 0887-4476
DOI - 10.1002/(sici)1098-2396(199804)28:4<322::aid-syn8>3.0.co;2-b
Subject(s) - dopamine transporter , transporter , serotonin transporter , serotonin plasma membrane transport proteins , ligand (biochemistry) , dopamine , binding site , chemistry , biochemistry , serotonin , biogenic amine , dopamine plasma membrane transport proteins , pharmacology , biology , receptor , endocrinology , gene
[ 125 I]RTI‐55 is a cocaine analog with high affinity for dopamine (DA) and serotonin (5‐HT) transporters. Quantitative ligand binding studies revealed a novel high affinity [ 125 I]RTI‐55 binding site assayed under 5‐HT transporter (SERT) conditions which has low affinity for almost all classic biogenic amine transporter ligands, including high affinity 5‐HT transporter inhibitors such as paroxetine, but which retains high affinity for cocaine analogs. This site, termed SERT site2 for its detection under 5‐HT transporter conditions (not for an association with the SERT) occurs in monkey caudate, human caudate, and guinea pig caudate membranes, but not in rat caudate membranes. SERT site2 is distinguished from the DA transporter (DAT) and SERT by several criteria, including a distinct ligand‐selectivity profile, the inability to detect SERT site2 in cells stably expressing the cloned human DAT, and insensitivity to irreversible ligands which inhibit [ 125 I]RTI‐55 binding to the DAT and SERT. Perhaps the most striking finding about SERT site2 is that a wide range of representative antidepressant agents have very low affinity for SERT site2 . The affinity of cocaine for this site is not very different from the concentration cocaine achieves in the brain at pharmacological doses. Viewed collectively with the observation that ligands with high affinity for SERT site2 are mostly cocaine analogs, these data lead us to speculate that actions of cocaine which differ from those of classic biogenic amine uptake inhibitors may be mediated in part via SERT site2 . Synapse 28:322–338, 1998. Published 1998 Wiley‐Liss, Inc.