The effects of phenelzine and other monoamine oxidase inhibitor antidepressants on brain and liver I2 imidazoline‐preferring receptors
Authors: Alemany Regina , Olmos Gabriel , García‐Sevilla Jesús A. 
Published: July 2012

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.
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%).
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).
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.
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.
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.