Ceramide-induced alterations in dopamine transporter function.
The purpose of this study was to determine the effects of ceramide on dopamine and serotonin (5-HT, 5-hydroxytryptamine) transporters. Exposure of rat striatal synaptosomes to C2-ceramide caused a reversible, concentration-dependent decrease in plasmalemmal dopamine uptake. In contrast, ceramide exposure increased striatal 5-HT synaptosomal uptake. This increase did not appear to be due to an increased uptake by the 5-HT transporter. Rather, the increase appeared to result from an increase in 5-HT transport through the dopamine transporter, an assertion evidenced by findings that this increase: (1) does not occur in hippocampal synaptosomes (i.e., a preparation largely devoid of dopamine transporters), (2) occurs in striatal synaptosomes prepared from para-chloroamphetamine-treated rats (i.e., a preparation lacking 5-HT transporters), (3) is attenuated by pretreatment with methylphenidate (i.e., a relatively selective dopamine reuptake inhibitor) and (4) is inhibited by exposure to exogenous dopamine (i.e., which presumably competes for uptake with 5-HT). Taken together, these results reveal that ceramide is a novel modulator of monoamine transporter function, and may alter the affinity of dopamine transporters for its primary substrate.
Riddle
Evan L
EL
Department of Pharmacology and Toxicology, University of Utah, Room 201, 30 South 2000 East, Salt Lake City, UT 84112, USA.
Rau
Kristi S
KS
Topham
Matthew K
MK
Hanson
Glen R
GR
Fleckenstein
Annette E
AE
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002518:Ceramides / Q000378:metabolism / Q000494:pharmacology*; D003042:Cocaine / Q000031:analogs & derivatives* / Q000378:metabolism; D004298:Dopamine / Q000493:pharmacokinetics; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000502:physiology*; D008774:Methylphenidate / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000493:pharmacokinetics; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D014316:Tritium
D002518:Ceramides; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C109343:dihydroceramide; D014316:Tritium; D008774:Methylphenidate; D012701:Serotonin; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine; D004298:Dopamine