Reboxetine: functional inhibition of monoamine transporters and nicotinic acetylcholine receptors.
The present study determined whether repeated administration of the antidepressant and selective norepinephrine (NE) uptake inhibitor reboxetine resulted in an adaptive modification of the function of the NE transporters (NETs), serotonin (5-HT) transporters, or dopamine (DA) transporters. Because antidepressants may be effective tobacco smoking cessation agents and because antidepressants have recently been shown to interact with nicotinic acetylcholine receptors (nAChRs), the interaction of reboxetine with nAChRs was also evaluated. Repeated administration of reboxetine (10 mg/kg i.p., twice daily for 14 days) did not alter the potency or selectivity of reboxetine inhibition of [(3)H]NE, [(3)H]DA, or [(3)H]5-HT uptake into striatal or hippocampal synaptosomes (IC(50) values = 8.5 nM, 89 microM, and 6.9 microM, respectively). In a separate series of experiments, reboxetine did not inhibit (K(i) > 1 microM) [(3)H]methyllycaconitine, [(3)H]cytisine, or [(3)H]epibatidine binding to rat whole brain membranes. However, at concentrations that did not exhibit intrinsic activity, reboxetine potently inhibited (IC(50) value = 7.29 nM) nicotine-evoked [(3)H]NE overflow from superfused hippocampal slices via a noncompetitive mechanism. In the latter experiments, the involvement of NET was eliminated by inclusion of desipramine (10 microM) in the superfusion buffer. Reboxetine also inhibited (IC(50) value = 650 nM) nicotine-evoked (86)Rb(+) efflux at reboxetine concentrations that did not exhibit intrinsic activity in this assay. Thus, in addition to inhibition of NET function, reboxetine inhibits nAChR function, suggesting that it may have potential as a smoking cessation agent.
College of Pharmacy, University of Kentucky, Lexington, KY 40536-0082, USA.
Dennis K
DK
Miller
Erik H F
EH
Wong
M Dathan
MD
Chesnut
Linda P
LP
Dwoskin
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D001692:Biological Transport; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D003342:Corpus Striatum / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D006624:Hippocampus / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D009025:Morpholines / Q000494:pharmacology*; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents / Q000378:metabolism; D018733:Nicotinic Antagonists / Q000494:pharmacology; D050484:Norepinephrine Plasma Membrane Transport Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077593:Reboxetine; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000502:physiology*; D050486:Serotonin Plasma Membrane Transport Proteins; D027981:Symporters / Q000037:antagonists & inhibitors*; D013574:Synaptosomes / Q000378:metabolism*; D014316:Tritium
D018759:Adrenergic Uptake Inhibitors; D015306:Biogenic Monoamines; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009025:Morpholines; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D018733:Nicotinic Antagonists; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011978:Receptors, Nicotinic; D050486:Serotonin Plasma Membrane Transport Proteins; C493226:Slc6a2 protein, rat; C493232:Slc6a4 protein, rat; D027981:Symporters; D014316:Tritium; D000077593:Reboxetine