Alpha 2-autoreceptors and alpha 2-heteroreceptors modulating tyrosine and tryptophan hydroxylase activity in the rat brain in vivo: an investigation into the alpha 2-adrenoceptor subtypes.
The subtype determination of auto- and hetero-alpha 2-adrenoceptors modulating the synthesis of noradrenaline (NA) and serotonin (5-HT), respectively, was assessed using the accumulation of 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition as a measure of the rate of tyrosine and tryptophan hydroxylation in the rat brain in vivo. In the cerebral cortex and hippocampus, Org 3770 (non-selective alpha 2-adrenoceptor antagonist, 0.5-10 mg/kg, i.p.) increased (43%-58%) and clonidine (non-selective alpha 2-adrenoceptor agonist, 1 mg/kg) decreased (37%-49%) the synthesis of dopa. Also the antagonist ARC 239 (alpha 2B/C selective, 5-40 mg/kg) increased the synthesis of dopa in cortex (39%-46%) and hippocampus (17%-85%). In contrast, the antagonist BRL 44408 (alpha 2D selective, 1-10 mg/kg) did not increase the synthesis of dopa in cortex, and increased it modestly in hippocampus only. The agonist guanoxabenz (alpha 2B/C selective, 0.03-3 mg/kg) decreased the synthesis of dopa in both brain regions (20%-65%), whereas the agonist oxymetazoline (alpha 2D selective, 0.1-3 mg/kg) failed to do so. These results indicated that the alpha 2-autoreceptors that modulate the synthesis of dopa/NA are probably associated with the alpha 2B/C-subtypes. In cortex and hippocampus, clonidine decreased (35%-53%) the synthesis of 5-HTP but Org 3770 failed to induce the opposite effect (except the 2 mg/kg dose in cortex). BRL 44408 markedly increased the synthesis of 5-HTP in cortex (113%-148%) but not in hippocampus. Similarly, also ARC239 increased the formation of 5-HTP in cortex (36%-48%) but not in hippocampus, where it was decreased (30%-55%). Oxymetazoline decreased the synthesis of 5-HTP in hippocampus (28%-30%) but failed to do so in cortex. Guanoxabenz in the low dose range (0.03-0.3 mg/kg) did not decrease the synthesis of 5-HTP in any brain region. These results indicated that the alpha 2-heteroreceptors that modulate the synthesis of 5-HTP/5-HT may well be different from the proposed alpha 2B/C-autoreceptors modulating the synthesis of dopa/NA. These alpha 2-heteroreceptors appear to be associated with the alpha 2D-subtype.
Esteban
S
S
Departament de Biologia Fonamental i Ciències de la Salut, Universitat de les Illes Balears, Palma de Mallorca, Spain.
Lladó
J
J
García-Sevilla
J A
JA
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects; D004295:Dihydroxyphenylalanine / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D054833:Isoindoles; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives / Q000494:pharmacology; D000078785:Mirtazapine; D009638:Norepinephrine / Q000096:biosynthesis*; D010879:Piperazines / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000096:biosynthesis*; D014365:Tryptophan Hydroxylase / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000502:physiology
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D006634:Histamine H1 Antagonists; D007093:Imidazoles; D007211:Indoles; D054833:Isoindoles; D007546:Isoquinolines; D010879:Piperazines; D011804:Quinolines; D008803:Mianserin; D012701:Serotonin; C000470:EEDQ; D004295:Dihydroxyphenylalanine; D000078785:Mirtazapine; D014446:Tyrosine 3-Monooxygenase; D014365:Tryptophan Hydroxylase; C032994:AR-C239; D009638:Norepinephrine; C072125:BRL 44408