On the relationship between the dopamine transporter and the reinforcing effects of local anesthetics in rhesus monkeys: practical and theoretical concerns.
BACKGROUND
Drugs that are self-administered appear to vary in their potency and effectiveness as positive reinforcers. Understanding mechanisms that determine relative effectiveness of drugs as reinforcers will enhance our understanding of drug abuse.


OBJECTIVE
The hypothesis of the present study was that differences among dopamine transporter (DAT) ligands in potency and effectiveness as a positive reinforcers were related to potency and effectiveness as DA uptake inhibitors. Accordingly, self-administration of a group of local anesthetics that are DAT ligands was compared to their effects as DA uptake blockers in vitro in brain tissue.


METHODS
Rhesus monkeys were allowed to self-administer cocaine and other local anesthetics i.v. under a progressive-ratio schedule. The same compounds were compared in standard in vitro DA uptake assays using monkey caudate tissue.


RESULTS
The rank order of both potency and effectiveness as reinforcers was cocaine > dimethocaine > procaine > chloroprocaine. Tetracaine did not maintain self-administration. For inhibiting DA uptake, the potency order was cocaine > dimethocaine > tetracaine > procaine > chloro-procaine. At maximum, these compounds were equally effective in blocking DA uptake. Lidocaine did not inhibit DA uptake.


CONCLUSIONS
The potency of local anesthetics as positive reinforcers is likely related to their potency as DA uptake inhibitors. Variation in their effectiveness as positive reinforcers was not a function of differences in effectiveness as DA uptake blockers, but may be related to relative potency over the concentrations that are achieved in vivo. Effects at sodium channels may limit the reinforcing effects of local anesthetics.
Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS 39216-4505, USA.
K M
KM
Wilcox
J K
JK
Rowlett
I A
IA
Paul
G A
GA
Ordway
W L
WL
Woolverton
D000779:Anesthetics, Local / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism*; D003216:Conditioning, Operant / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D005260:Female; D008253:Macaca mulatta; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012055:Reinforcement Schedule; D012054:Reinforcement, Psychology; D012646:Self Administration
D000779:Anesthetics, Local; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D004298:Dopamine