Role of the dopamine transporter and the sodium channel in the cocaine-like discriminative stimulus effects of local anesthetics in rats.
BACKGROUND
Local anesthetics bind to the dopamine transporter (DAT), inhibit dopamine (DA) uptake and have been reported to have cocaine-like discriminative stimulus effects. The hypothesis of the present study was that affinity at the DAT and potency as a DA uptake blocker determines potency as a cocaine-like discriminative stimulus among local anesthetics, and maximum DA uptake inhibition determines maximum cocaine-like discriminative stimulus effects.


OBJECTIVE
Cocaine-like discriminative potency was compared to DAT affinity and DA uptake inhibition potency, and maximum cocaine-like discriminative stimulus effects were compared to maximum DA uptake inhibition for procaine, chloroprocaine, dimethocaine, tetracaine and lidocaine.


METHODS
Discriminative stimulus effects were determined in two groups of rats using 10 mg/kg and 3.0 mg/kg cocaine training doses. DAT affinity and DA uptake inhibition effects were determined in vitro in rat caudate nucleus tissue. Additionally, sodium channel affinity was determined in rat frontal cortex tissue.


RESULTS
In the 10 mg/kg group, none of the local anesthetics fully substituted for cocaine and all decreased response rate. Rate decreasing potencies were positively correlated with sodium channel affinities. In the low training dose group, all the local anesthetics except tetracaine substituted fully for cocaine. Discriminative potencies were positively correlated with sodium channel affinities. Maximum DA uptake inhibition did not adequately predict maximum discriminative stimulus effects.


CONCLUSIONS
Cocaine-like discriminative stimulus effects of local anesthetics were more prominent at a low than at a high training dose of cocaine. Sodium channels seem to have a direct influence on discriminative effects at low cocaine doses, whereas they have an indirect influence on discriminative effects at high cocaine doses by decreasing response rates.
Wilcox
K M
KM
Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 N. State Street, Jackson, MS 39216, USA.
Paul
I A
IA
Ordway
G A
GA
Woolverton
W L
WL
D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000502:physiology*; D009419:Nerve Tissue Proteins; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*
D000779:Anesthetics, Local; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493216:Slc6a3 protein, rat; D015222:Sodium Channels; D003042:Cocaine