title: Activation of beta2- and beta3-adrenergic receptors increases brain tryptophan.
abstract: Brain tryptophan concentrations are increased by various stressful treatments, an effect that can be prevented by beta-adrenoceptor antagonists. This study aimed to determine the beta-adrenergic subtype responsible for the tryptophan response. Male CD-1 mice received intraperitoneal injections of nonselective and subtype-selective beta-adrenergic antagonists 20 min before subtype-selective beta-agonists. Selected brain regions were dissected for analysis of tryptophan content by high-performance liquid chromatography with electrochemical detection. The beta(2)-selective agonist clenbuterol (0.3 mg/kg) induced increases in brain tryptophan that reached a peak ( approximately 60%) 1 h following injection and small but statistically significant increases ( approximately 20%) in 5-hydroxyindoleacetic acid: serotonin ratios 2 h following injection. The beta(1)-selective agonist dobutamine (10 mg/kg) produced less robust increases ( approximately 40%) in brain tryptophan, whereas the beta(3)-selective agonists BRL 37344 (0.2 mg/kg (+/-)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino)propyl] phenoxy]acetic acid sodium)) and CL 316243 [0.1 mg/kg disodium 5-[(2R)-2-([(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino)propyl]-1,3-benzodioxole-2,2-dicarboxylate)] resulted in larger increases (80 to 100%). Pretreatment with the beta(2)-selective antagonist ICI 118551 (0.5 mg/kg (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxyl]-3-[(1-methylethyl)amino]-2-butanol) attenuated the increases in tryptophan induced by both clenbuterol (0.1 mg/kg) and dobutamine (10 mg/kg). Pretreatment with the beta(1/2)-selective antagonist propranolol (2.5 mg/kg), the beta(3)-selective antagonist SR 59230A [1.5, 2.5, 5, or 20 mg/kg (3-(2-ethylphenoxy)-1[1S)-1,2,3,4-tertahydronaphth-1-yl-amino]-(2S)-2-propanol oxalate)], or ICI 118551 (0.5 mg/kg) did not prevent the BRL 37344-induced increase in brain tryptophan, whereas the beta(1/2/3)-antagonist bupranolol (10 mg/kg) attenuated it. CL 316243 had no effect on brain tryptophan in beta(3)-receptor knockout mice, whereas clenbuterol increased brain tryptophan, indicating that beta-adrenergic modulation of brain tryptophan occurs in the absence of beta(3)-receptors. We conclude that activation of either beta(2)- or beta(3)-adrenergic receptors, but not beta(1)-adrenergic receptors, increases mouse brain tryptophan content.
authors.affiliation: Department of Pharmacology and Therapeutics, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932, USA. nlenar@lsuhsc.edu
authors.forename: Natalie R
authors.initials: NR
authors.lastname: Lenard
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Gettys
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Dunn
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D004280:Dobutamine / Q000494:pharmacology; D004983:Ethanolamines / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D022702:Receptors, Adrenergic, beta-3 / Q000172:deficiency / Q000235:genetics; D012701:Serotonin / Q000096:biosynthesis; D014364:Tryptophan / Q000378:metabolism*
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D004983:Ethanolamines; D022702:Receptors, Adrenergic, beta-3; D012701:Serotonin; D004280:Dobutamine; C057368:BRL 37344; D014364:Tryptophan