Interaction of cocaine and dopamine transporter inhibitors on behavior and neurochemistry in monkeys.
Drugs that target the dopamine transporter (DAT) have been proposed as pharmacotherapies to treat cocaine abuse. Accordingly, it is paramount to understand pharmacological interactions between cocaine and DAT inhibitors. The present study characterized acute interactions between cocaine and several DAT inhibitors (RTI-177, FECNT, RTI-112) that differed in selectivity for monoamine transporters on operant behavior and in vivo neurochemistry in squirrel monkeys. RTI-177 and FECNT, two DAT inhibitors with low affinity at norepinephrine transporters (NET), produced dose-dependent stimulant effects on behavior maintained by a fixed-interval schedule of stimulus termination. Compared to cocaine, RTI-177 and FECNT had a slower onset and longer duration of action. In vivo microdialysis in the caudate nucleus of awake monkeys confirmed dose-dependent increases in extracellular dopamine that corresponded to behavioral effects. Among the drugs characterized, RTI-112 is reportedly the least selective for binding to DAT, NET, and serotonin transporters (SERT). Interestingly, RTI-112 failed to produce significant behavioral-stimulant effects, and its effects on extracellular dopamine were highly variable across subjects. The results indicate that the pharmacological profile of DAT inhibitors may be influenced by actions at multiple monoamine transporters. Importantly, there was little evidence of additivity on behavioral or neurochemical measures when cocaine was administered in combination with behavioral-stimulant doses of the DAT inhibitors.
Ginsburg
Brett C
BC
Yerkes National Primate Research Center, Emory University, 954 Gatewood Road NE, Atlanta, GA 30329, USA.
Kimmel
Heather L
HL
Carroll
F Ivy
FI
Goodman
Mark M
MM
Howell
Leonard L
LL
D000818:Animals; D003042:Cocaine / Q000378:metabolism / Q000494:pharmacology*; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009662:Nortropanes / Q000378:metabolism / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects* / Q000502:physiology; D012453:Saimiri; D014326:Tropanes / Q000378:metabolism / Q000494:pharmacology
C410211:2-carbomethoxy-3-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane; C095429:3-(4'-chlorophenyl)-2-(3'-phenylisoxazol-5'-yl)tropane; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009662:Nortropanes; D014326:Tropanes; D003042:Cocaine