title: Effects of imidazoline receptor ligands on monoamine synthesis in the rat brain in vivo.
abstract: This study was designed to assess the effects of imidazoline drugs on putative presynaptic imidazoline receptors modulating brain monoamine synthesis in vivo. The accumulation of 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition was used as a measure of the rate of tyrosine and tryptophan hydroxylation in various brain regions of naive rats and after irreversible alpha2-adrenoceptor inactivation with EEDQ (1.6 mg/kg, i.p., 6 h). Clonidine (1-3 mg/kg), moxonidine (1-10 mg/kg) and rilmenidine (10 mg/kg) (mixed I1/alpha2 agonists) decreased dopa and 5-HTP synthesis in the cerebral cortex (14%-81%), hippocampus (27%-84%) and/or striatum (29%-56%), but these inhibitory effects were abolished in N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)-treated rats. Similarly, the stimulatory effect of efaroxan (mixed I1/alpha2 antagonist; 10 mg/kg) on dopa synthesis in the cortex (77%) and hippocampus (57%) was abolished by EEDQ. The selective I1-ligand 2-endo-amino-3-exoisopropylbicyclo-heptane (AGN-192403; 5-10 mg/kg) did not modify dopa or 5-HTP synthesis in any brain region in naive or EEDQ-treated rats. Idazoxan (mixed I2/alpha2 antagonist; 20 mg/kg) increased dopa synthesis in the cortex (111%) and hippocampus (87%), but the stimulatory effects were abolished by EEDQ. Moreover, idazoxan and efaroxan decreased 5-HTP synthesis in the cortex (12%-34%) and hippocampus (30%-34%) in a manner sensitive to blockade by the 5-HT1A receptor antagonist WAY 100135. The selective I2-igands 2-(2-benzofuranyl)-2-imidazoline (2-BFI; 20 mg/kg) and 2-styryl-2-imidazoline (LSL 61122; 10 mg/kg) did not alter the synthesis of dopa or 5-HTP in the cortex or hippocampus. In striatum, 2-BFI (1-20 mg/kg) dose-dependently decreased dopa synthesis (ED50: 5.9 mg/kg), reduced dopamine levels (6%-36%) and increased those of its metabolites DOPAC (15%-95%) and HVA (24%-74%). The inhibitory effect of 2-BFI on dopa/dopamine synthesis in striatum remained unchanged after alkylation of imidazoline receptors with isothiocyanatobenzyl imidazoline (IBI; 60 mg/kg, 6 h) or blockade of these receptors with 2-(2-ethyl 2,3-dihydro-2-benzofuranyl)-2-imidazole (KU-14R; 7-20 mg/kg). Therefore, most imidazoline drugs modulated the synthesis of brain monoamines through interaction with alpha2-adrenoceptors or 5-HT1A receptors. The results do not provide functional evidence for the existence of presynaptic imidazoline receptors regulating the synthesis of monoamines in the rat brain.
authors.affiliation: Department of Biology, University of the Balearic Islands, Palma de Mallorca, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Sastre-Coll
authors.forename: S
authors.initials: S
authors.lastname: Esteban
authors.forename: J A
authors.initials: JA
authors.lastname: García-Sevilla
mesh_terms: D006916:5-Hydroxytryptophan / Q000096:biosynthesis; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000096:biosynthesis*; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004295:Dihydroxyphenylalanine / Q000096:biosynthesis; D007093:Imidazoles / Q000378:metabolism* / Q000494:pharmacology; D054755:Imidazoline Receptors; D008024:Ligands; D008297:Male; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D017661:Receptors, Presynaptic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D014365:Tryptophan Hydroxylase / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000317:Adrenergic alpha-Antagonists; D001572:Benzofurans; D015306:Biogenic Monoamines; D007093:Imidazoles; D054755:Imidazoline Receptors; D008024:Ligands; D011804:Quinolines; D018341:Receptors, Adrenergic, alpha-2; D011955:Receptors, Drug; D017661:Receptors, Presynaptic; C000470:EEDQ; D004295:Dihydroxyphenylalanine; C103723:2-(2-benzofuranyl)-2-imidazoline; D006916:5-Hydroxytryptophan; D014446:Tyrosine 3-Monooxygenase; D014365:Tryptophan Hydroxylase