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Catecholamine synthesis and metabolism in the central nervous system of mice lacking α 2 ‐adrenoceptor subtypes
Author(s) -
VieiraCoelho MA,
Serrão MP,
Afonso J,
Pinto CE,
Moura E
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00375.x
Subject(s) - catecholamine , medicine , endocrinology , dopamine , catabolism , tyrosine hydroxylase , monoamine oxidase , aromatic l amino acid decarboxylase , metabolism , chemistry , catechol o methyl transferase , enzyme , biology , biochemistry , genotype , gene
Background and purpose: This study investigates the role of α 2 ‐adrenoceptor subtypes, α 2A , α 2B and α 2C , on catecholamine synthesis and catabolism in the central nervous system of mice. Experimental approach: Activities of the main catecholamine synthetic and catabolic enzymes were determined in whole brains obtained from α 2A ‐, α 2B ‐ and α 2C ‐adrenoceptor knockout (KO) and C56Bl\7 wild‐type (WT) mice. Key results: Although no significant differences were found in tyrosine hydroxylase activity and expression, brain tissue levels of 3,4‐dihydroxyphenylalanine were threefold higher in α 2A ‐ and α 2C ‐adrenoceptor KO mice. Brain tissue levels of dopamine and noradrenaline were significantly higher in α 2A and α 2C KOs compared with WT [WT: 2.8 ± 0.5, 1.1 ± 0.1; α 2A KO: 6.9 ± 0.7, 1.9 ± 0.1; α 2B KO: 2.3 ± 0.2, 1.0 ± 0.1; α 2C KO: 4.6 ± 0.8, 1.5 ± 0.2 nmol·(g tissue) −1 , for dopamine and noradrenaline respectively]. Aromatic L‐amino acid decarboxylase activity was significantly higher in α 2A and α 2C KO [WT: 40 ± 1; α 2A : 77 ± 2; α 2B : 40 ± 1; α 2C : 50 ± 1, maximum velocity ( V max ) in nmol·(mg protein) −1 ·h −1 ], but no significant differences were found in dopamine β‐hydroxylase. Of the catabolic enzymes, catechol‐ O ‐methyltransferase enzyme activity was significantly higher in all three α 2 KO mice [WT: 2.0 ± 0.0; α 2A : 2.4 ± 0.1; α 2B : 2.2 ± 0.0; α 2C : 2.2 ± 0.0 nmol·(mg protein) −1 ·h −1 ], but no significant differences were found in monoamine oxidase activity between all α 2 KOs and WT mice. Conclusions and implications: In mouse brain, deletion of α 2A ‐ or α 2C ‐adrenoceptors increased cerebral aromatic L‐amino acid decarboxylase activity and catecholamine tissue levels. Deletion of any α 2 ‐adrenoceptor subtypes resulted in increased activity of catechol‐ O ‐methyltransferase. Higher 3,4‐dihydroxyphenylalanine tissue levels in α 2A and α 2C KO mice could be explained by increased 3,4‐dihydroxyphenylalanine transport.