The effects of phenelzine and other monoamine oxidase inhibitor antidepressants on brain and liver I2 imidazoline-preferring receptors.
1. The binding of [3H]-idazoxan in the presence of 10(-6) M (-)-adrenaline was used to quantitate I2 imidazoline-preferring receptors in the rat brain and liver after chronic treatment with various irreversible and reversible monoamine oxidase (MAO) inhibitors. 2. Chronic treatment (7-14 days) with the irreversible MAO inhibitors, phenelzine (1-20 mg kg-1, i.p.), isocarboxazid (10 mg kg-1, i.p.), clorgyline (3 mg kg-1, i.p.) and tranylcypromine (10 mg kg-1, i.p.) markedly decreased (21-71%) the density of I2 imidazoline-preferring receptors in the rat brain and liver. In contrast, chronic treatment (7 days) with the reversible MAO-A inhibitors, moclobemide (1 and 10 mg kg-1, i.p.) or chlordimeform (10 mg kg-1, i.p.) or with the reversible MAO-B inhibitor Ro 16-6491 (1 and 10 mg kg-1, i.p.) did not alter the density of I2 imidazoline-preferring receptors in the rat brain and liver; except for the higher dose of Ro 16-6491 which only decreased the density of these putative receptors in the liver (38%). 3. In vitro, phenelzine, clorgyline, 3-phenylpropargylamine, tranylcypromine and chlordimeform displaced the binding of [3H]-idazoxan to brain and liver I2 imidazoline-preferring receptors from two distinct binding sites. Phenelzine, 3-phenylpropargylamine and tranylcypromine displayed moderate affinity (KiH = 0.3-6 microM) for brain and liver I2 imidazoline-preferring receptors; whereas chlordimeform displayed high affinity (KiH = 6 nM) for these receptors in the two tissues studied, Clorgyline displayed very high affinity for rat brain (KiH = 40 pM) but not for rat liver I2 imidazoline-preferring receptors (KiH = 169 nM). 4. Preincubation of cortical or liver membranes with phenelzine (10-4 M for 30 min) did not alter the total density of I2 imidazoline-preferring receptors, indicating that this irreversible MAO inhibitor does not irreversibly bind to I2 imidazoline-preferring receptors. In contrast, preincubation with 10-6 Mclorgyline reduced by 40% the Bmax of [3H]-idazoxan to brain and liver I2 imidazoline-preferring receptors.5. Chronic treatment (7 days) with the inducers of cytochrome P-450 enzymes phenobarbitone (40 or 80 mg kg-1, i.p.), 3-methylcholanthrene (20 mg kg-1, i.p.) or 2-methylimidazole (40 mg kg-1, i.p.) did not alter the binding parameters of [3H]-idazoxan to brain and liver 12 imidazoline-preferring receptors.The compound SKF 525A, a potent inhibitor of cytochrome P-450 enzymes which forms a tight but reversible complex with the haemoprotein, completely displaced with moderate affinity (KiH = 2-10 microM)the specific binding of [3H]-idazoxan to brain and liver 12 imidazoline-preferring receptors. Preincubation of total liver homogenates with 3 x 10-4 M phenelzine in the presence of 10-3 M NADH, a treatment that irreversibly inactivates the haeme group of cytochrome P-450, did not reduce the density of liver I2 imidazoline-preferring receptors. These results discounted a possible interaction of [3H]-idazoxan with the haeme group of cytochrome P-450 enzymes.6. Together the results indicate that the down-regulation of I2 imidazoline-preferring receptors is associated with an irreversible inactivation of MAO (at least in the brain) that is not related either to the affinity of the MAO inhibitors for I2 imidazoline-preferring receptors or to an irreversible binding to these putative receptors. These findings indicate a novel effect of irreversible MAO inhibitors in the brain and suggest a new target for these compounds that could be of relevance in the treatment of depression, a disease in which an increased density of brain I2 imidazoline-preferring receptors has been reported.
Alemany
R
R
Department of Fundamental Biology and Health Sciences, University of the Balearic Islands, Palma de Mallorca, Spain.
Olmos
G
G
García-Sevilla
J A
JA
D000317:Adrenergic alpha-Antagonists / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001549:Benzamides / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002742:Chlorphenamidine / Q000008:administration & dosage / Q000494:pharmacology; D003010:Clorgyline / Q000008:administration & dosage / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004146:Dioxanes / Q000378:metabolism; D019329:Idazoxan; D007093:Imidazoles / Q000378:metabolism; D054755:Imidazoline Receptors; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D007520:Isocarboxazid / Q000008:administration & dosage / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020912:Moclobemide; D008996:Monoamine Oxidase Inhibitors / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D010293:Pargyline / Q000031:analogs & derivatives; D010624:Phenelzine / Q000008:administration & dosage / Q000494:pharmacology*; D011437:Propylamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000187:drug effects* / Q000378:metabolism; D014191:Tranylcypromine / Q000008:administration & dosage / Q000494:pharmacology
D000317:Adrenergic alpha-Antagonists; D000928:Antidepressive Agents; D001549:Benzamides; D004146:Dioxanes; D007093:Imidazoles; D054755:Imidazoline Receptors; D008996:Monoamine Oxidase Inhibitors; D011437:Propylamines; D011955:Receptors, Drug; D007520:Isocarboxazid; D014191:Tranylcypromine; C094031:3-phenylpropargylamine; C051040:Ro 16-6491; D003577:Cytochrome P-450 Enzyme System; D010293:Pargyline; D002742:Chlorphenamidine; D003010:Clorgyline; D010624:Phenelzine; D020912:Moclobemide; D019329:Idazoxan