Vol. 302, Issue 2, 687-695, August 2002

Reboxetine: Functional Inhibition of Monoamine Transporters and Nicotinic Acetylcholine Receptors

Dennis K. Miller, Erik H. F. Wong, M. Dathan Chesnut and Linda P. Dwoskin

College of Pharmacy, University of Kentucky, Lexington, Kentucky (D.K.M., M.D.C., L.P.D.); and Pharmacia Corporation, Kalamazoo, Michigan (E.H.F.W.)

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 [³H]NE, [³H]DA, or [³H]5-HT uptake into striatal or hippocampal synaptosomes (IC₅₀ values = 8.5 nM, 89 µM, and 6.9 µM, respectively). In a separate series of experiments, reboxetine did not inhibit (K_i > 1 µM) [³H]methyllycaconitine, [³H]cytisine, or [³H]epibatidine binding to rat whole brain membranes. However, at concentrations that did not exhibit intrinsic activity, reboxetine potently inhibited (IC₅₀ value = 7.29 nM) nicotine-evoked [³H]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 µM) in the superfusion buffer. Reboxetine also inhibited (IC₅₀ value = 650 nM) nicotine-evoked ⁸⁶Rb⁺ 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.