Self-administration of cocaine and the cocaine analog RTI-113: relationship to dopamine transporter occupancy determined by PET neuroimaging in rhesus monkeys.
Dopaminergic mechanisms are thought to play a central role in the reinforcing effects of cocaine. The present study examined the reinforcing effects of 3beta-(4-chlorophenyl)tropane-2beta-carboxylic acid phenyl ester (RTI-113), a long-acting, selective, high-affinity dopamine uptake inhibitor. Additionally, the effects of RTI-113 pretreatment on cocaine self-administration were determined. Monkeys were trained to respond under a second-order schedule for intravenous cocaine administration (0.10 or 0.17 mg/kg/infusion). When responding was stable, cocaine (0.0030-1.0 mg/kg/infusion) and RTI-113 (0.010-0.30 mg/kg/infusion) were substituted for the cocaine training dose. Cocaine and RTI-113 were equipotent for their reinforcing effects. However, cocaine maintained higher response rates in two of the three monkeys tested. When administered as a pretreatment, RTI-113 (0.10-0.30 mg/kg) dose-dependently reduced responding maintained by two doses of cocaine. Drug effects on behavior were related to dopamine transporter (DAT) occupancy in monkey striatum during neuroimaging with positron emission tomography. DAT occupancy was determined by displacement of 8-(2-[(18)F]fluroethyl)2beta-carbomethoxy-3beta-(4-chlorophenyl)nortropane (FECNT). DAT occupancy was between 65-76% and 94-99% for doses of cocaine and RTI-113 that maintained maximum response rates, respectively. DAT occupancy did not differ markedly across RTI-113 pretreatment doses and ranged between 72-84%. The results suggest that the pharmacokinetic profile of RTI-113 (i.e., long-acting) may influence its ability to maintain self-administration, and therefore its abuse liability. Additionally, high DAT occupancy is required for RTI-113 to reduce cocaine-maintained responding.
Wilcox
K M
KM
Yerkes Regional Primate Research Center, Emory University, Atlanta, Georgia 30322, USA. kwilcox@rmy.emory.edu
Lindsey
K P
KP
Votaw
J R
JR
Goodman
M M
MM
Martarello
L
L
Carroll
F I
FI
Howell
L L
LL
D000818:Animals; D003042:Cocaine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D005260:Female; D008253:Macaca mulatta; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D017072:Neostriatum / Q000000981:diagnostic imaging / Q000187:drug effects*; D009419:Nerve Tissue Proteins; D009662:Nortropanes; D012646:Self Administration; D014055:Tomography, Emission-Computed
C410211:2-carbomethoxy-3-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009662:Nortropanes; C114870:RTI-113; D003042:Cocaine; D004298:Dopamine