Studies of the biogenic amine transporters. VII. Characterization of a novel cocaine binding site identified with [I-125]RTI-55 in membranes prepared from human, monkey and guinea pig caudate
[I-125]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 [I-125]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 SERTsite2 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. SERTsite2 is distinguished from the DA transporter (DAT) and SERT by several criteria, including a distinct ligand-selectivity profile, the inability to detect SERTsite2 in cells stably expressing the cloned human DAT, and insensitivity to irreversible ligands which inhibit [I-125]RTI-55 binding to the DAT and SERT. Perhaps the most striking finding about SERTsite2 is that a nide range of representative antidepressant agents have very low affinity for SERTsite2. 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 SERTsite2 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 SERTsite2. (C) 1998 Wiley-Liss, Inc
Rothman, RB., Silverthorn, ML., Glowa, JR., Matecka, D., Rice, KC., Carroll, F., ... Dersch, CM. (1998). Studies of the biogenic amine transporters. VII. Characterization of a novel cocaine binding site identified with [I-125]RTI-55 in membranes prepared from human, monkey and guinea pig caudate. Synapse, 28(4), 322-338.