BINDING AND COMPETITIVE-INHIBITION OF AMINE UPTAKE AT POSTSYNAPTIC NEURONS (TRANSPORT-P) BY TRICYCLIC ANTIDEPRESSANTS

1 We have provided evidence for a novel amine uptake process for which prazosin is a substrate in postsynaptic neurones, characterized by a paradoxical increase in accumulation of the radioligand when the conce ntration of the unlabelled drug is increased above 10(-7) M. This incr ease is due to activation of a proton-dependent, vacuolar type-ATPase- linked uptake process which is blocked by desipramine but is resistant to reserpine. We have now examined the effects of tricyclic antidepre ssants on this uptake system in a cell line derived from hypothalamic peptidergic neurones, known to be innervated by noradrenergic nerve te rminals in vivo. 2 [H-3]-imipramine bound to the cells and was displac ed by unlabelled imipramine, desipramine, amitriptyline and nortriptyl ine. The data fitted a single binding site model. This is the first de monstration of antidepressant binding sites in postsynaptic neurones. 3 There was no increase in the binding of [H-3]-imipramine at high con centrations of unlabelled imipramine, suggesting that antidepressants inhibit uptake but are not themselves accumulated by peptidergic gonad otrophin releasing hormone neurones. 4 Accumulation of prazosin was co mpetitively inhibited by antidepressants. Tertiary amines were slightl y more potent than secondary amines and the presence of a nitrogen ato m in the heterocyclic ring enhanced blocking activity. 5 The affinitie s of the antidepressants for the uptake process are within the range o f plasma concentrations that are observed during therapeutic use of th ese compounds. Since it is likely that this uptake process has a physi ological function, its inhibition by antidepressants may provide a new avenue for investigating the mechanism of action of these compounds.