title: [3H]nisoxetine--a radioligand for noradrenaline reuptake sites: correlation with inhibition of [3H]noradrenaline uptake and effect of DSP-4 lesioning and antidepressant treatments.
abstract: Nisoxetine is a potent and selective inhibitor of noradrenaline uptake into noradrenergic neurones. [3H]Nisoxetine binding to rat frontal cortical membranes was of high affinity. The binding data of both competition and saturation studies fitted a single site binding model. [3H]Nisoxetine binding was potently inhibited by the selective noradrenaline uptake inhibitors desipramine and protriptyline. In addition, a very good correlation was obtained between the ability of 25 monoamine reuptake inhibitors and related compounds both to inhibit [3H]nisoxetine binding and to inhibit [3H]noradrenaline uptake in rat frontal cortex. DSP-4 (10-100 mg/kg, i.p.) dose-dependently depleted cortical noradrenaline concentrations (51-100%), with no significant effects on 5-HT and dopamine. These depletions, which were used as a marker of loss of noradrenergic nerve terminals, were associated with a dose-dependent decrease in the number of [3H]nisoxetine binding sites (20-97%) with no change in binding affinity. Furthermore, a good correlation was obtained between cortical noradrenaline concentrations and the number of [3H]nisoxetine binding sites. These data support the view that [3H]nisoxetine binds to a single population of homogeneous sites associated with the noradrenaline transporter complex. Using this ligand, the effects of repeated administration of both antidepressant drugs with a range of pharmacological actions and of electroconvulsive shock on noradrenaline reuptake sites were examined. The number and affinity of [3H]nisoxetine binding sites were unaltered by all treatments. It is unlikely, therefore, that antidepressant therapy would produce adaptive changes in noradrenaline uptake sites.
authors.affiliation: Knoll Pharmaceuticals Research Department, Nottingham, U.K.
authors.forename: S C
authors.initials: SC
authors.lastname: Cheetham
authors.forename: J A
authors.initials: JA
authors.lastname: Viggers
authors.forename: S A
authors.initials: SA
authors.lastname: Butler
authors.forename: M R
authors.initials: MR
authors.lastname: Prow
authors.forename: D J
authors.initials: DJ
authors.lastname: Heal
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001667:Binding, Competitive; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005625:Frontal Lobe / Q000187:drug effects; D007700:Kinetics; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000928:Antidepressive Agents; D005473:Fluoxetine; C011386:nisoxetine; D009638:Norepinephrine