Inhibitory effect of selective serotonin reuptake inhibitors on the vesicular monoamine transporter 2.
The neuronal vesicular monoamine transporter (VMAT2) is the target molecule of action of some psychostimulants, such as methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA). The present study examined the effect of antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), on VMAT2 activity by measuring adenosine triphosphate-dependent [(3)H]dopamine uptake into synaptic vesicles prepared from rat striatum. SSRIs, fluoxetine, paroxetine, and fluvoxamine, inhibited vesicular [(3)H]dopamine uptake in vitro. The rank order of potency was reserpine>>fluoxetine, paroxetine>fluvoxamine, methamphetamine>MDMA. Moreover, kinetic analysis revealed that inhibition by reserpine, a typical VMAT2 inhibitor, was uncompetitive, decreasing maximum velocity and affinity for dopamine. Inhibition by fluoxetine was noncompetitive, only decreasing maximum velocity for dopamine. These results suggest that fluoxetine inhibited the activity of VMAT2 by a mechanism different from that of reserpine and did not directly interact with the active site of VMAT2.
Division of Psychobiology, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan.
Satoshi
S
Yasumoto
Kohei
K
Tamura
Junichi
J
Karasawa
Ryota
R
Hasegawa
Kazutaka
K
Ikeda
Toshifumi
T
Yamamoto
Hideko
H
Yamamoto
D000818:Animals; D004298:Dopamine / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology; D016666:Fluvoxamine / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology; D017374:Paroxetine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012110:Reserpine / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000187:drug effects* / Q000378:metabolism*
D004298:Dopamine; D005473:Fluoxetine; D016666:Fluvoxamine; D006220:Haloperidol; D008694:Methamphetamine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D017374:Paroxetine; D012110:Reserpine; D017367:Selective Serotonin Reuptake Inhibitors; D050493:Vesicular Monoamine Transport Proteins; C493454:Slc18a2 protein, rat