Reboxetine: A pharmacologically potent, selective, and specific norepinephrine reuptake inhibitor

Background: Reboxetine is a potent antidepressant, with efficacy comparable to that of imipramine, desipramine, and fluoxetine, and has improved side- effect profile. The basis of its efficacy and improved tolerability is soug ht through studies of reboxetine in a number of pharmacological models of d epression. Methods: Pharmacological selectivity for uptake systems was defined by upta ke and binding assay for the three monoamine uptake sites. Specificity was determined in 39 different receptor and 6 enzyme assays. In vivo selectivit y was defined by measurement of neuronal firing rates in the locus coeruleu s, dorsal raphe, and substantia nigra. Reserpine-induced blepharospasm and hypothermia, clonidine-induced hypothermia, defined reboxetine's in vivo ph armacology. Reboxetine's antidepressant potential was evaluated behaviorall y by the tail-suspension test, forced swimming, and the DRL72 operant respo nding test. Results: Reboxetine is a potent, selective, and specific norepinephrine reu ptake inhibitor (selective NRI) as determined by both in vitro and in vivo measurements. Unlike desipramine or imipramine, reboxetine has weak affinit y (Ki > 1000 nmol/L) for muscarinic, histaminergic H1, adrenergic alpha(1), and dopaminergic D-2 receptors. In vivo action of reboxetine is entirely c onsistent with the pharmacological action of an antidepressant with prefere ntial action at the norepinephrine reuptake site. Reboxetine showed an anti depressant profile in all tests of antidepressant activity used. Significan t decreases in immobility were observed in the tail suspension test and beh avioral despair test. Increased efficiency in responding was observed in th e DRL72 test. Conclusions: Reboxetine is a potent, selective, and specific noradrenergic reuptake inhibitor. It has a superior pharmacological selectivity to existi ng tricyclic antidepressants and selective serotonin reuptake inhibitors wh en tested in a large number of in vitro and in vivo systems. Given the phar macological profile, reboxetine is expected to be a selective and potent to ol for psychopharmacological research. The use of reboxetine in the clinic will also help clarify the role norepinephrine plays in depression. Biol Ps ychiatry 2000;47:818-829 (C) 2000 Society of Biological Psychiatry.