title: Catecholamine synthesis and metabolism in the central nervous system of mice lacking alpha-adrenoceptor subtypes.
abstract: OBJECTIVE
  This study investigates the role of alpha(2)-adrenoceptor subtypes, alpha(2A), alpha(2B) and alpha(2C), on catecholamine synthesis and catabolism in the central nervous system of mice.
  
  
  METHODS
  Activities of the main catecholamine synthetic and catabolic enzymes were determined in whole brains obtained from alpha(2A)-, alpha(2B)- and alpha(2C)-adrenoceptor knockout (KO) and C56Bl\7 wild-type (WT) mice.
  
  
  RESULTS
  Although no significant differences were found in tyrosine hydroxylase activity and expression, brain tissue levels of 3,4-dihydroxyphenylalanine were threefold higher in alpha(2A)- and alpha(2C)-adrenoceptor KO mice. Brain tissue levels of dopamine and noradrenaline were significantly higher in alpha(2A) and alpha(2C)KOs compared with WT [WT: 2.8 +/- 0.5, 1.1 +/- 0.1; alpha(2A)KO: 6.9 +/- 0.7, 1.9 +/- 0.1; alpha(2B)KO: 2.3 +/- 0.2, 1.0 +/- 0.1; alpha(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 alpha(2A) and alpha(2C)KO [WT: 40 +/- 1; alpha(2A): 77 +/- 2; alpha(2B): 40 +/- 1; alpha(2C): 50 +/- 1, maximum velocity (V(max)) in nmol.(mg protein)(-1).h(-1)], but no significant differences were found in dopamine beta-hydroxylase. Of the catabolic enzymes, catechol-O-methyltransferase enzyme activity was significantly higher in all three alpha(2)KO mice [WT: 2.0 +/- 0.0; alpha(2A): 2.4 +/- 0.1; alpha(2B): 2.2 +/- 0.0; alpha(2C): 2.2 +/- 0.0 nmol.(mg protein)(-1).h(-1)], but no significant differences were found in monoamine oxidase activity between all alpha(2)KOs and WT mice.
  
  
  CONCLUSIONS
  In mouse brain, deletion of alpha(2A)- or alpha(2C)-adrenoceptors increased cerebral aromatic L-amino acid decarboxylase activity and catecholamine tissue levels. Deletion of any alpha(2)-adrenoceptor subtypes resulted in increased activity of catechol-O-methyltransferase. Higher 3,4-dihydroxyphenylalanine tissue levels in alpha(2A) and alpha(2C)KO mice could be explained by increased 3,4-dihydroxyphenylalanine transport.
authors.affiliation: Institute of Pharmacology and Therapeutics, University of Porto, Porto, Portugal.
authors.forename: M A
authors.initials: MA
authors.lastname: Vieira-Coelho
authors.forename: M P
authors.initials: MP
authors.lastname: Serrão
authors.forename: J
authors.initials: J
authors.lastname: Afonso
authors.forename: C E
authors.initials: CE
authors.lastname: Pinto
authors.forename: E
authors.initials: E
authors.lastname: Moura
mesh_terms: D000166:Acridines / Q000494:pharmacology; D058669:Adrenergic alpha-2 Receptor Antagonists; D000818:Animals; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000378:metabolism; D001692:Biological Transport; D001921:Brain / Q000378:metabolism*; D002394:Catechol O-Methyltransferase / Q000378:metabolism; D002395:Catecholamines / Q000096:biosynthesis / Q000378:metabolism*; D045744:Cell Line, Tumor; D004299:Dopamine beta-Hydroxylase / Q000378:metabolism; D006801:Humans; D007980:Levodopa / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008995:Monoamine Oxidase / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015016:Yohimbine / Q000494:pharmacology
chemical_list: C547768:ADRA2A protein, human; C547771:ADRA2B protein, human; C547774:ADRA2C protein, human; D000166:Acridines; C547769:Adra2a protein, mouse; C547772:Adra2b protein, mouse; C547775:Adra2c protein, mouse; D058669:Adrenergic alpha-2 Receptor Antagonists; D002395:Catecholamines; C518829:JP-1302; D010879:Piperazines; D018341:Receptors, Adrenergic, alpha-2; D015016:Yohimbine; D007980:Levodopa; D014446:Tyrosine 3-Monooxygenase; D004299:Dopamine beta-Hydroxylase; D008995:Monoamine Oxidase; D002394:Catechol O-Methyltransferase; D001142:Aromatic-L-Amino-Acid Decarboxylases
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