TY - JOUR
T1 - Evaluation of organic cation transporter 3 (SLC22A3) inhibition as a potential mechanism of antidepressant action
AU - Zhu, Hao Jie
AU - Appel, David I.
AU - Gründemann, Dirk
AU - Richelson, Elliott
AU - Markowitz, John S.
PY - 2012/4
Y1 - 2012/4
N2 - Organic cation transporter 3 (OCT3, SLC22A3) is a low-affinity, high-capacity transporter widely expressed in the central nervous system (CNS) and other major organs in both humans and rodents. It is postulated that OCT3 has a role in the overall regulation of neurotransmission and maintenance of homeostasis within the CNS. It is generally believed that all antidepressant drugs in current clinical use exert their primary therapeutic effects through inhibition of one or more of the high-affinity neuronal plasma membrane monoamine transporters, such as the norepinephrine transporter and the serotonin transporter. In the present study, we investigated the inhibitory effects of selected antidepressants on OCT3 activity in OCT3-transfected cells to evaluate whether OCT3 inhibition may at least in part contribute to the pharmacological effects of tested antidepressants. The studies demonstrated that all examined antidepressants inhibited OCT3-mediated uptake of the established OCT3 substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (4-Di-1-ASP) in a concentration-dependent manner. The IC 50 values were determined to be 4.7 μM, 7.4 μM, 12.0 μM, 18.6 μM, 11.2 μM, and 21.9 μM for desipramine, sertraline, paroxetine, amitriptyline, imipramine, and fluoxetine, respectively. Additionally, desipramine had an IC 50 value of 0.7 μM for the uptake of NE by OCT3, while the IC 50 value of sertraline was 2.3 μM for 5-HT uptake. Both desipramine and sertraline appeared to inhibit OCT3 activity via a non-competitive mechanism. In vivo studies are warranted to determine whether such effects on OCT3 inhibition are of sufficient magnitude to contribute to the overall therapeutic effects of antidepressants.
AB - Organic cation transporter 3 (OCT3, SLC22A3) is a low-affinity, high-capacity transporter widely expressed in the central nervous system (CNS) and other major organs in both humans and rodents. It is postulated that OCT3 has a role in the overall regulation of neurotransmission and maintenance of homeostasis within the CNS. It is generally believed that all antidepressant drugs in current clinical use exert their primary therapeutic effects through inhibition of one or more of the high-affinity neuronal plasma membrane monoamine transporters, such as the norepinephrine transporter and the serotonin transporter. In the present study, we investigated the inhibitory effects of selected antidepressants on OCT3 activity in OCT3-transfected cells to evaluate whether OCT3 inhibition may at least in part contribute to the pharmacological effects of tested antidepressants. The studies demonstrated that all examined antidepressants inhibited OCT3-mediated uptake of the established OCT3 substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (4-Di-1-ASP) in a concentration-dependent manner. The IC 50 values were determined to be 4.7 μM, 7.4 μM, 12.0 μM, 18.6 μM, 11.2 μM, and 21.9 μM for desipramine, sertraline, paroxetine, amitriptyline, imipramine, and fluoxetine, respectively. Additionally, desipramine had an IC 50 value of 0.7 μM for the uptake of NE by OCT3, while the IC 50 value of sertraline was 2.3 μM for 5-HT uptake. Both desipramine and sertraline appeared to inhibit OCT3 activity via a non-competitive mechanism. In vivo studies are warranted to determine whether such effects on OCT3 inhibition are of sufficient magnitude to contribute to the overall therapeutic effects of antidepressants.
KW - Antidepressant
KW - Depression
KW - Inhibition
KW - Organic cation transporter 3
KW - Uptake-1
KW - Uptake-2
UR - http://www.scopus.com/inward/record.url?scp=84863393063&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84863393063&partnerID=8YFLogxK
U2 - 10.1016/j.phrs.2012.01.008
DO - 10.1016/j.phrs.2012.01.008
M3 - Article
C2 - 22342816
AN - SCOPUS:84863393063
SN - 1043-6618
VL - 65
SP - 491
EP - 496
JO - Pharmacological Research
JF - Pharmacological Research
IS - 4
ER -