THE EFFECTS OF PHENELZINE AND OTHER MONOAMINE-OXIDASE INHIBITOR ANTIDEPRESSANTS ON BRAIN AND LIVER I-2 IMIDAZOLINE-PREFERRING RECEPTORS

1 The binding of [H-3]-idazoxan in the presence of 10(-6) M (-)-adrena line was used to quantitate I-2 imidazoline-preferring receptors in th e rat brain and liver after chronic treatment with various irreversibl e and reversible monoamine oxidase (MAO) inhibitors. 2 Chronic treatme nt (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 decre ased (21-71%) the density of I-2 imidazoline-preferring receptors in t he rat brain and liver. In contrast, chronic treatment (7 days) with t he 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 in hibitor Ro 16-6491 (1 and 10 mg kg(-1), i.p.) did not alter the densit y 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 dens ity of these putative receptors in the liver (38%). 3 In vitro, phenel zine, clorgyline, 3-phenylpropargylamine, tranylcypromine and chlordim eform displaced the binding of ra]-idazoxan to brain and liver It imid azoline-preferring receptors from two distinct binding sites. Phenelzi ne, 3-phenylpropargylamine and tranylcypromine displayed moderate affi nity (K-iH = 0.3-6 mu M) for brain and liver I-2 imidazoline-preferrin g receptors; whereas chlordimeform displayed high affinity (K-iH = 6 n M) for these receptors in the two tissues studied, Clorgyline displaye d very high affinity for rat brain (K-iH = 40 pM) but not for rat live r I, imidazoline-preferring receptors (K-iH = 169 nM). 4 Preincubation of cortical or liver membranes with phenelzine (10(-4) M for 30 min) did not alter the total density of I, imidazoline-preferring receptors , indicating that this irreversible MAO inhibitor does not irreversibl y bind to It imidazoline-preferring receptors. In contrast, preincubat ion with 10(-6) M clorgyline reduced by 40% the B-max of [H-3]-idazoxa n to brain and liver It imidazoline-preferring receptors. 5 Chronic tr eatment (7 days) with the inducers of cytochrome P-450 enzymes Phenoba rbitone (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 after the bi nding parameters of [3H]-idazoxan to brain and liver It imidazoline-pr eferring receptors. The compound SKF 525A, a potent inhibitor of cytoc hrome P-450 enzymes which forms a tight but reversible complex with th e haemoprotein, completely displaced with moderate affinity (k(iH), = 2-10 mu M) the specific binding of [H-3]-idazoxan to brain and liver I -2 imidazoline-preferring receptors. Preincubation of total liver homo genates with 3 x 10(-4) M phenelzine in the presence of 10(-3) M NADH, a treatment that irreversibly inactivates the haeme group of cytochro me P-450, did not reduce the density of liver 12 imidazoline-preferrin g receptors. These results discounted a possible interaction of [3H]-i dazoxan with the haeme group of cytochrome P-450 enzymes. 6 Together t he results indicate that the down-regulation of It imidazoline-preferr ing receptors is associated with an irreversible inactivation of MAO ( at least in the brain) that is not related either to the affinity of t he MAO inhibitors for I-2 imidazoline-preferring receptors or to an ir reversible binding to these putative receptors. These findings indicat e a novel effect of irreversible MAO inhibitors in the brain and sugge st a new target for these compounds that could be of relevance in the treatment of depression, a disease in which an increased density of br ain It imidazoline-preferring receptors has been reported.