Alpha 2-autoreceptor-mediated modulation of tyrosine hydroxylase activity in noradrenergic regions of the rat brain in vivo.
The physiological importance of brain alpha 2-adrenoceptors in controlling the activity of tyrosine hydroxylase in noradrenergic regions was investigated using the accumulation of 3,4-dihydroxyphenylalanine (DOPA) after decarboxylase inhibition as a measure of the rate of tyrosine hydroxylation (and synthesis of noradrenaline) in vivo. In the hypothalamus and cerebral cortex, clonidine (0.025-1 mg/kg, i.p.) decreased (18%-43%) and idazoxan (0.1-80 mg/kg, i.p.) increased (20%-73%) the synthesis of DOPA in a dose-dependent manner. Moreover, pretreatment with idazoxan (0.1 mg/kg) antagonized the effect of clonidine (0.1 mg/kg) in the hypothalamus. After treatment with reserpine (5 mg/kg, s.c., 18 h before decapitation) and depletion of noradrenaline, clonidine (0.5 mg/kg) continued to decrease (50%-55%) but idazoxan (20 mg/kg) failed to increase the synthesis of DOPA, which suggested the involvement of an alpha-auto-receptor mechanism. Acute treatments of rats (not exposed to reserpine) with a wide variety of adrenoceptor agonists such as guanfacine 6, B-HT920, xylazine, bromoxidine (1 mg/kg) and antagonists such as yohimbine, phentolamine, prazosin (10 or 20 mg/kg) resulted in significant decreases (15%-55%) or increases (21%-99%) in the synthesis of DOPA in both brain regions. However, other agonists (oxymetazoline, azepexole, tramazoline, methoxamine) and antagonists (tolazoline, dihydroergotamine, phenoxybenzamine, propranolol) did not modify the synthesis of DOPA. In the hypothalamus and cerebral cortex the effects of the drugs were consistent with the selectivity of alpha-adrenoceptor agonists and antagonists (except prazosin) for an alpha 2-adrenoceptor. The results also suggest that the alpha 2-autoreceptor that modulates the synthesis of noradrenaline in the rat brain appears to belong to the prazosin-sensitive alpha 2B-subtype.
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Departamento de Neurociencias, Universidad del País Vasco, Bizkaia, Spain.
García-Sevilla
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JA
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D003000:Clonidine / Q000378:metabolism / Q000494:pharmacology*; D004295:Dihydroxyphenylalanine / Q000378:metabolism; D004146:Dioxanes / Q000494:pharmacology*; D019329:Idazoxan; D007274:Injections, Intraperitoneal; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D011942:Receptors, Adrenergic, alpha; D004295:Dihydroxyphenylalanine; D014446:Tyrosine 3-Monooxygenase; D003000:Clonidine; D009638:Norepinephrine; D019329:Idazoxan