Journal
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
Volume 90, Issue 3, Pages 453-462Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.pbb.2008.03.032
Keywords
cocaine; drug discrimination; PET neuroimaging; phenyltropane; putamen; reinstatement; rhesus monkey; self-administration
Funding
- Intramural NIH HHS [Z01 DA000517] Funding Source: Medline
- NCRR NIH HHS [P51 RR000165, P51 RR000165-477444, RR00165] Funding Source: Medline
- NIDA NIH HHS [K02 DA000517, R37 DA010344, R01 DA010344-10, DA13326, R01 DA002519, K01 DA015092-04, R01 DA002519-23A2, K01 DA015092, DA02519, P01 DA014528-050001, U19 DA013326, DA10344, R01 DA005477, R37 DA005477, R01 DA010344, P01 DA014528, DA15092, DA 05477, K02 DA000517-08, R37 DA005477-18, U19 DA013326-04, DA14528] Funding Source: Medline
- NIMH NIH HHS [R33 MH066622-05, MH66622, R33 MH066622, R21 MH066622] Funding Source: Medline
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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-ad ministration 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. (C) 2008 Elsevier Inc. All rights reserved.
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