The effects of phenelzine and other monoamine oxidase inhibitor antidepressants on brain and liver I 2 imidazoline‐preferring receptors

1 The binding of [ 3 H]‐idazoxan in the presence of 10 −6 m (−)‐adrenaline was used to quantitate I 2 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 I 2 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 I 2 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 [ 3 H]‐idazoxan to brain and liver I 2 imidazoline‐preferring receptors from two distinct binding sites. Phenelzine, 3‐phenylpropargylamine and tranylcypromine displayed moderate affinity ( K iH = 0.3–6 μ m ) for brain and liver I 2 imidazoline‐preferring receptors; whereas chlordimeform displayed high affinity ( K iH = 6 n m ) for these receptors in the two tissues studied, Clorgyline displayed very high affinity for rat brain ( K iH = 40 p m ) but not for rat liver I 2 imidazoline‐preferring receptors ( K iH = 169 n m ). 4 Preincubation of cortical or liver membranes with phenelzine (10 −4 m for 30 min) did not alter the total density of I 2 imidazoline‐preferring receptors, indicating that this irreversible MAO inhibitor does not irreversibly bind to I 2 imidazoline‐preferring receptors. In contrast, preincubation with 10 −6 m clorgyline reduced by 40% the B max of [ 3 H]‐idazoxan to brain and liver I 2 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 [ 3 H]‐idazoxan to brain and liver I 2 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 ( K iH = 2–10 μ m ) the specific binding of [ 3 H]‐idazoxan to brain and liver I 2 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 I 2 imidazoline‐preferring receptors. These results discounted a possible interaction of [ 3 H]‐idazoxan with the haeme group of cytochrome P‐450 enzymes. 6 Together the results indicate that the down‐regulation of I 2 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 I 2 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 I 2 imidazoline‐preferring receptors has been reported.