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.
Yerkes National Primate Research Center, Emory University, 954 Gatewood Rd. NE, Atlanta, GA 30329, USA.
Kimberly P
KP
Lindsey
Kristin M
KM
Wilcox
John R
JR
Votaw
Mark M
MM
Goodman
Christophe
C
Plisson
F Ivy
FI
Carroll
Kenner C
KC
Rice
Leonard L
LL
Howell
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