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.