title: 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-isothiocyanato-phenylethyl ester hydrochloride¿, an irreversible inhibitor of dopamine transporter (DAT) binding in vitro, on [125I]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 [3H]DAT and D1 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 KD for [125I]RTI-55 binding in vitro in striatal tissue, without affecting transporter maximum binding (Bmax). In contrast, 24 hr after administration, RTI-76 caused a dose-related decrease in striatal DAT Bmax without affecting KD, a decrease that reversed over the next several days. Transport of [3H]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 [3H]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 Bmax, as well as the concurrent decrease in [3H]DAT, were reversible, with the T1/2 of transporter recovery estimated to be 6 days.
authors.affiliation: National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, Maryland, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Fleckenstein
authors.forename: S
authors.initials: S
authors.lastname: Pögün
authors.forename: F I
authors.initials: FI
authors.lastname: Carroll
authors.forename: M J
authors.initials: MJ
authors.lastname: Kuhar
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D003042:Cocaine / Q000031:analogs & derivatives / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D014326:Tropanes / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C101790:RTI 76; C493216:Slc6a3 protein, rat; D014326:Tropanes; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine; D004298:Dopamine