title: Selective inhibition of monoamine neurotransmitter transporters by synthetic local anesthetics.
abstract: Synthetic local anesthetics (LAs) have been found to have cocaine-like characteristics with some psychotomimetic action, possibly through monoaminergic neurotransmission. To gain insight into the relation between LA action and monoamine transporters, we investigated the effect of synthetic LAs on neurotransmitter transporters, including monoamine transporters. We used cloned transporter cDNAs and examined transient functional expression in COS cells and stable expression in HeLa cells. Among the LAs tested, procaine and other ester-type LAs inhibited [3H]DA uptake and binding of [3H]2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane (CFT), a cocaine analogue, in COS cells expressing rat dopamine transporter (DAT). The inhibition was concentration-dependent. The inhibitory effect on [3H]DA uptake was reversible and not dependent on pH, as observed in HeLa cells stably expressing DAT. Procaine also inhibited uptake of norepinephrine (NE) and serotonin (5-HT) by the norepinephrine transporter (NET) or serotonin transporter (SERT) expressed in COS cells. On the other hand, procaine and other LAs had little or no effect on [3H]GABA and [3H]glutamate uptake in COS cells expressing mouse GABA or rat glutamate/aspartate transporter. IC50 values for [3H]DA uptake inhibition correlated well with those for [3H]CFT binding inhibition, but not with intrinsic anesthetic potency. Kinetic analysis of monoamine uptake inhibition by procaine in COS cells expressing rat DAT, NET or SERT revealed a competitive action similar to that of cocaine. These results demonstrate that certain LAs selectively inhibit monoamine transporters. This might contribute to the cocaine-like psychotomimetic action of certain LAs.
authors.affiliation: Department of Pharmacology, Hiroshima University School of Dentistry, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sato
authors.forename: S
authors.initials: S
authors.lastname: Kitayama
authors.forename: C
authors.initials: C
authors.lastname: Mitsuhata
authors.forename: T
authors.initials: T
authors.lastname: Ikeda
authors.forename: K
authors.initials: K
authors.lastname: Morita
authors.forename: T
authors.initials: T
authors.lastname: Dohi
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D019556:COS Cells; D002352:Carrier Proteins / Q000187:drug effects*; D003042:Cocaine / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000187:drug effects*; D026901:Membrane Transport Proteins; D051379:Mice; D009419:Nerve Tissue Proteins; D009638:Norepinephrine / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011343:Procaine / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D027981:Symporters; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000779:Anesthetics, Local; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493227:SLC6A2 protein, human; C493214:SLC6A3 protein, human; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C493228:Slc6a2 protein, mouse; C493226:Slc6a2 protein, rat; C493215:Slc6a3 protein, mouse; C493216:Slc6a3 protein, rat; C493231:Slc6a4 protein, mouse; C493232:Slc6a4 protein, rat; D027981:Symporters; D012701:Serotonin; D018698:Glutamic Acid; D011343:Procaine; D005680:gamma-Aminobutyric Acid; D003042:Cocaine; D009638:Norepinephrine