The effects of phenelzine and other monoamine oxidase inhibitor antidepressants on brain and liver I2 imidazoline‐preferring receptors

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Abstract
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 μm) 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 m clorgyline 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 I2 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 μm) the specific binding of [3H]-idazoxan to brain and liver I2 imidazoline-preferring receptors. Preincubation of total liver homogenates with 3 times 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.