PROLONGED DOPAMINE AND SEROTONIN TRANSPORTER INHIBITION AFTER EXPOSURE TO TROPANES

Cocaine and tropane analogs are known to interact with biogenic monoam ine transporters by inhibiting amine uptake. Previous in vivo studies have demonstrated that some of these tropanes produce a longer lasting behavioral effect compared with cocaine. We have previously examined several tropane analogs and found a difference in their relative affin ities for dopamine (DA) and serotonin (5-HT) transporters. The purpose of this study was to determine the recovery time of transporter funct ion in vitro and in vivo comparing cocaine with the tropane analogs WF -11 (PTT, selective for DA transporters), WF-31 (selective for 5-HT tr ansporters) and WF-23 (highly potent at both DA and 5-HT transporters) . In vitro, using primary rat brain cultures of either midbrain or rap he regions, the recovery of the ability to transport either [H-3]dopam ine or [H-3]serotonin, respectively was evaluated at 0, 3, 24, 48, 120 and 240 h after a 1 h exposure to cocaine and tropane analogs. The tr opanes exhibited clearance half-lives ranging from 12 to 69 h, while c ocaine, on the other hand, exhibited a clearance half-life of approxim ate to 6 h. In studies utilizing [I-125]RTI-55 binding, intraperitonea l injections of cocaine and WF-23 into the rat resulted in striatal cl earance half-lives ex vivo that were almost identical to those obtaine d in vitro. These data suggest that the tropanes bind to and reduce tr ansporter function for prolonged periods of time (up to 10-fold longer than cocaine) and those compounds with the highest affinity may produ ce a pseudo-irreversible inhibition of transporter function. (C) 1998 Elsevier Science Ltd. All rights reserved.