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Subcellular Site of Action of Imipramine in Rodent Brain
Author(s) -
Wood Martyn D.,
Wyllie Michael G.
Publication year - 1986
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.1986.tb00611.x
Subject(s) - imipramine , desipramine , synaptosome , chemistry , microsome , synaptic vesicle , membrane , pharmacology , biochemistry , medicine , endocrinology , biophysics , vesicle , in vitro , biology , hippocampus , antidepressant , pathology , alternative medicine
To determine the site of action of imipramine, the subcellular distribution of [ 3 H]imipramine in rodents was followed after both in vivo administration and in vitro incubation with tissue slices under “physiological” conditions. Total [ 3 H]imipramine (10–1,000 n M ) binding was associated with all primary fractions, but in particular with the nuclear (P 1 ) and mitochondrial (P 2 ) pellets and the synaptosomal (P 2 B) and myelin (P 2 A) fractions; Using an excess of imipramine to define any nonspecific interactions, a specific association was observed mainly in those fractions containing isolated nerve terminals and to a lesser extent with the purified myelin fraction. Preparation of subsynaptosomal fractions by osmotic lysis indicated that [ 3 H]imipramine was associated with the synaptic vesicle and microsomal fractions and also with synaptosomal membranes. The degree of binding to the vesicular and microsomal fractions was increased with the length of preparation time, whereas there was an inverse relationship between the length of preparation and the amount bound to the synaptosomal membrane fraction. There was no evidence of an intrasynaptosomal accumulation of [ 3 H]imipramine at concentrations up to 1,000 n M . [ 3 H]2‐Nitroimipramine, a slowly dissociating imipramine derivative, was exclusively located in synaptic membrane fractions. Prior treatment of rats with a combination of 5,7‐dihydroxytryptamine and desipramine reduced 5‐hydroxytryptamine levels and the levels of [ 3 H]imipramine associated with the synaptosomal fractions to the same extent. It is concluded that imipramine is associated with a binding site localised on 5‐hydroxytryptaminergic nerve terminals and that there is a redistribution to other sites (vesicular and microsomal) during the isolation procedure.