Effects of dopamine transporter inhibitors on cocaine self-administration in rhesus monkeys: relationship to transporter occupancy determined by positron emission tomography neuroimaging.
The dopamine transporter (DAT) is a critical recognition site for cocaine and contributes to its significant abuse liability. Accordingly, the development of compounds that target the DAT represents a logical approach in the pharmacological treatment of cocaine abuse. The present study characterized the effects of DAT inhibitors as pretreatments in rhesus monkeys trained to self-administer cocaine under a second-order schedule of i.v. drug delivery. The drugs also were substituted for cocaine to characterize their effectiveness in maintaining drug self-administration. Positron emission tomography neuroimaging with [(18)F]8-(2-[(18)F]fluoroethyl)-2beta-carbomethoxy-3beta-(4-chlorophenyl) nortropane established the DAT occupancy associated with behaviorally relevant doses of each drug. The drugs studied included a selective DAT inhibitor, [1-(2[bis(4-fluorophenyl-) methoxy]ethyl)-4-(3-phenylpropyl)piperazine] bimesylate hydrate (GBR 12909); an inhibitor with equal potency at dopamine and norepinephrine transporters, [3beta-(4-chlorophenyl)tropane-2beta-(3-phenylisoxazol-5-yl)] HCl (RTI-177); and a nonselective inhibitor of dopamine, norepinephrinem and serotonin transporters, [(-)-3beta-(3'-methyl-4-chlorophenyl)tropane-2beta-carboxylic acid methyl ester] tartrate (RTI-112). All drugs produced dose-related reductions in cocaine self-administration. Doses of GBR 12909 and RTI-177 that reduced responding by 50% (ED(50)) resulted in DAT occupancies of 67 +/- 5 and 73 +/- 5%, respectively. In contrast, DAT occupancy was below the limit of detection for the ED(50) dose of RTI-112. Both GBR 12909 and RTI-177 reliably maintained drug self-administration, and DAT occupancies at doses that maintained peak rates of responding were 57 +/- 1 and 92 +/- 7%, respectively. In contrast, RTI-112 failed to maintain robust drug self-administration in any subject. The results indicate that selective DAT inhibitors may require high DAT occupancy to reduce cocaine self-administration and maintain drug self-administration. Moreover, the behavioral profile of DAT inhibitors may be influenced by actions at other monoamine transporters.
Lindsey
Kimberly P
KP
Yerkes National Primate Research Center, Emory University, 954 Gatewood Rd. NE, Atlanta, GA 30329, USA.
Wilcox
Kristin M
KM
Votaw
John R
JR
Goodman
Mark M
MM
Plisson
Christophe
C
Carroll
F Ivy
FI
Rice
Kenner C
KC
Howell
Leonard L
LL
D000758:Anesthesia; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000188:drug therapy*; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000627:therapeutic use*; D007530:Isoflurane / Q000494:pharmacology; D008253:Macaca mulatta; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012646:Self Administration; D014055:Tomography, Emission-Computed; D014326:Tropanes / Q000627:therapeutic use
C095429:3-(4'-chlorophenyl)-2-(3'-phenylisoxazol-5'-yl)tropane; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C432869:RTI 112; D014326:Tropanes; D007530:Isoflurane; D003042:Cocaine