Recovery of dopamine transporter binding and function after intrastriatal administration of the irreversible inhibitor RTI-76 {3 beta-(3p-chlorophenyl)tropan-2 beta-carboxylic acid p-isothiocyanatophenylethyl ester hydrochloride}

Abstract

Effects of in vivo, intrastriatal administration of RTI-76 {3 beta-(3-p-chlorophenyl)tropan-2 beta-carboxylic acid p-isothiocyanatophenylethyl ester hydrochloride}, an irreversible inhibitor of dopamine transporter (DAT) binding in vitro, on [I-125]RTI-55 {3 beta[4-iodophenyl]tropan-2 beta-carboxylic acid methyl ester tartrate} binding to striatal DAT in vitro were examined in male rats. Effects on [H-3]DAT and D-1, dopamine receptor binding in vitro after intrastriatal RTI-76 injection were also determined. One hour after direct intrastriatal injection, RTI-76 caused a dose-related increase in K-D for [I-125]RTI-55 binding in vitro in striatal tissue, without affecting transporter maximum binding (B-max). In contrast, 24 hr after administration, RTI-76 caused a dose-related decrease in striatal DAT B-max without affecting K-D, a decrease that reversed over the next several days. Transport of [H-3]dopamine into synaptosomes was decreased similarly. Intrastriatal injection of reversible inhibitors of DAT, such as cocaine or WIN-35428 {3 beta-[4-fluorophenyl]tropan-2 beta-carboxylic acid methyl ester tartrate}, was without effect on transporter binding 1 and 6 days after administration. RTI-76 had little effect on [H-3]SCH-23390 {R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro- 1H-3-benzazepine} binding 1 or 24 hr after intrastriatal injection, indicating at least some selectivity of RTI-76 for DAT. The RTI-76-induced decrease in B-max as well as the concurrent decrease in [H-3]DAT, were reversible,with the T-1/2 of transporter recovery estimated to be 6 days