Relationship between rate of drug uptake in brain and behavioral pharmacology of monoamine transporter inhibitors in rhesus monkeys.
Although inhibition of dopamine transporters (DAT) and the subsequent increase in dopamine clearly play a role in the effects of psychomotor stimulants, the reinforcing effectiveness of DAT inhibitors varies. Previous studies suggest that pharmacokinetic and pharmacodynamic properties of these drugs account for this variability. The present studies compared the time course and behavioral effects of five phenyltropane analogs of cocaine with high affinity for DAT and varying time courses of action in rhesus monkeys. The rate of drug uptake in putamen was measured using positron emission tomography neuroimaging. The rank order of the time to peak drug uptake was cocaine<RTI-336<RTI-150<RTI-113<RTI-177. Cocaine and all five analogs fully substituted for the cocaine cue in animals trained to discriminate cocaine from saline. All of the drugs were self-administered under a progressive-ratio schedule of drug self-administration and reinstated previously extinguished self-administration maintained under a second-order schedule. The time to peak drug uptake corresponded closely with the time to peak discriminative stimulus effects, and there was a trend for the time of peak drug uptake to correspond negatively with the peak number of drug infusions. Collectively, these results indicate that the rate of drug entry in brain can play an important role in the behavioral pharmacology of psychomotor stimulants.
Kimmel
Heather L
HL
Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322, USA. Heather.Kimmel@emory.edu
Negus
S Stevens
SS
Wilcox
Kristin M
KM
Ewing
Sarah B
SB
Stehouwer
Jeffrey
J
Goodman
Mark M
MM
Votaw
John R
JR
Mello
Nancy K
NK
Carroll
F Ivy
FI
Howell
Leonard L
LL
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000000981:diagnostic imaging; D001923:Brain Chemistry / Q000187:drug effects*; D003042:Cocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D008253:Macaca mulatta; D008297:Male; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D012055:Reinforcement Schedule; D012646:Self Administration; D019966:Substance-Related Disorders / Q000523:psychology
D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D019275:Radiopharmaceuticals; D003042:Cocaine