Comparison of effects of dual transporter inhibitors on monoamine transporters and extracellular levels in rats.
Compounds that block both serotonin (5-HT) and norepinephrine (NE) transporters have been proposed to have improved antidepressant efficacy. We compared the ability of four dual transporter inhibitors-chlorimipramine, duloxetine, milnacipran and venlafaxine-to block monoamine transporters in vitro and in vivo and increase extracellular monoamines in rat brain. Inhibition of radioligand binding to clonal human monoamine transporters in vitro and in vivo in rats was determined. Extracellular concentrations of 5-HT and NE in rat prefrontal cortex (PFC) were quantified using the microdialysis technique. All compounds blocked binding to human 5-HT and NE transporters, although chlorimipramine and venlafaxine had markedly greater affinity for 5-HT than NE transporters. In vivo, chlorimipramine and duloxetine potently blocked both transporters, milnacipran blocked both with lower potency and venlafaxine only blocked the 5-HT transporter. Chlorimipramine and duloxetine increased robustly and approximately equally monoamine extracellular concentrations. Milnacipran produced only small increases in NE, whereas venlafaxine increased 5-HT markedly at the lower doses and both monoamines at high doses. Thus, the dual transporter inhibitors blocked 5-HT and NE transporters in vitro and in vivo with varying potency. Chlorimipramine, duloxetine, and high dose venlafaxine acted as dual transporter inhibitors in rat PFC and increased extracellular concentrations of the monoamines, indicating functional dual transporter inhibition.
Koch
Susanne
S
Lilly Neuroscience Research Division, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Hemrick-Luecke
Susan K
SK
Thompson
Linda K
LK
Evans
David C
DC
Threlkeld
Penny G
PG
Nelson
David L
DL
Perry
Kenneth W
KW
Bymaster
Frank P
FP
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects; D002352:Carrier Proteins / Q000378:metabolism*; D002997:Clomipramine / Q000494:pharmacology; D003511:Cyclohexanols / Q000494:pharmacology; D003521:Cyclopropanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000068736:Duloxetine Hydrochloride; D005110:Extracellular Space / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D017551:Microdialysis; D000078764:Milnacipran; D009638:Norepinephrine / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology; D000069470:Venlafaxine Hydrochloride; D019805:alpha-Methyltyrosine / Q000494:pharmacology; D010133:p-Chloroamphetamine / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D015306:Biogenic Monoamines; D002352:Carrier Proteins; D002997:Clomipramine; D003511:Cyclohexanols; D003521:Cyclopropanes; D000068736:Duloxetine Hydrochloride; D000078764:Milnacipran; D009638:Norepinephrine; D012701:Serotonin; D018490:Serotonin Agents; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes; D000069470:Venlafaxine Hydrochloride; D019805:alpha-Methyltyrosine; D010133:p-Chloroamphetamine