High-affinity binding of β-carbolines to imidazoline I2B receptors and MAO-A in rat tissues: Norharman blocks the effect of morphine withdrawal on DOPA/noradrenaline synthesis in the brain

Abstract This study was designed to determine the affinity and binding profile of β-carbolines for imidazoline I 2 receptors and catalytic sites of monoamine oxidase (MAO)-A/B in rat brain and liver. The aim was also directed to assess the in vivo effects of norharman (β-carboline) and LSL 60101 (I 2 ligand) on brain 3,4-dihydroxyphenylalanine (DOPA) synthesis in morphine-dependent rats. Competition experiments against [ 3 H]2-BFI revealed that β-carbolines recognize the high- and low-affinity components of the brain imidazoline I 2 receptor with the rank order of potency ( K iH in nM): noreleagnine (12) > norharman (20) > harmalol (82) > harmaline (177) ≫ harmine (630) > harman (700) ≫ FG-7142 (> 100,000). In liver, this rank was different: harmine (51) > harmaline (103) = noreleagnine (103) ≫ harmalol (1290) > harman (2000) ≫ norharman (12,382) ≫ FG-7142 (> 100,000). In brain and liver, competition curves for β-carbolines against [ 3 H]Ro41-1049 (MAO-A) and [ 3 H]Ro19-6327 (MAO-B) were monophasic and resulted in different drug potencies for the two MAO isozymes (higher affinities for MAO-A) and in similar pharmacological profiles in both tissues. In morphine-dependent rats, naloxone (2 mg/kg, 2 h)-precipitated withdrawal increased the synthesis of DOPA in the cerebral cortex and hippocampus (50%). Pretreatment with norharman (20 mg/kg) or LSL 60101 (20 mg/kg) (30 min before naloxone) fully prevented the stimulatory effect of opiate withdrawal on DOPA synthesis. Norharman and LSL 60101 also attenuated the severity of the withdrawal syndrome. The results indicate that β-carbolines bind with high affinity to imidazoline I 2B receptors, and similarly to I 2 ligands (LSL 60101) can block the behavioural and biochemical effects of opiate withdrawal.