title: High-affinity binding of beta-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 beta-carbolines for imidazoline I2 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 (beta-carboline) and LSL 60101 (I2 ligand) on brain 3,4-dihydroxyphenylalanine (DOPA) synthesis in morphine-dependent rats. Competition experiments against [3H]2-BFI revealed that beta-carbolines recognize the high- and low-affinity components of the brain imidazoline I2 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 beta-carbolines against [3H]Ro41-1049 (MAO-A) and [3H]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 beta-carbolines bind with high affinity to imidazoline I2B receptors, and similarly to I2 ligands (LSL 60101) can block the behavioural and biochemical effects of opiate withdrawal.
authors.affiliation: Laboratori de Neurofarmacologia, Institut Universitari d'Investigació en Ciències de la Salut, Universitat de les Illes Balears, Ctra. Valldemossa km 7.5, E-07122, Palma de Mallorca, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Miralles
authors.forename: Susana
authors.initials: S
authors.lastname: Esteban
authors.forename: Antonio
authors.initials: A
authors.lastname: Sastre-Coll
authors.forename: David
authors.initials: D
authors.lastname: Moranta
authors.forename: Víctor José
authors.initials: VJ
authors.lastname: Asensio
authors.forename: Jesús Andrés
authors.initials: JA
authors.lastname: García-Sevilla
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002243:Carbolines / Q000378:metabolism* / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006247:Harmine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007093:Imidazoles / Q000378:metabolism / Q000494:pharmacology; D054755:Imidazoline Receptors; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism*; D009020:Morphine / Q000494:pharmacology; D009021:Morphine Dependence / Q000150:complications; D009270:Naloxone / Q000494:pharmacology; D009638:Norepinephrine / Q000096:biosynthesis; D010848:Picolinic Acids / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology; D014316:Tritium; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D001572:Benzofurans; D002243:Carbolines; D007093:Imidazoles; D054755:Imidazoline Receptors; C095677:LSL 60101; D010848:Picolinic Acids; D011955:Receptors, Drug; D013844:Thiazoles; D014316:Tritium; D009270:Naloxone; C063456:Ro 41-1049; C059303:lazabemide; D006247:Harmine; D004295:Dihydroxyphenylalanine; C009804:tryptoline; C103723:2-(2-benzofuranyl)-2-imidazoline; D009020:Morphine; C010262:norharman; D014446:Tyrosine 3-Monooxygenase; D008995:Monoamine Oxidase; D009638:Norepinephrine