Vol. 305, Issue 2, 653-659, May 2003

Activation of ₂- and ₃-Adrenergic Receptors Increases Brain Tryptophan

Natalie R. Lenard, Thomas W. Gettys and Adrian J. Dunn

Department of Pharmacology and Therapeutics and School of Graduate Studies, Louisiana State University Health Sciences Center, Shreveport, Louisiana (N.R.L., A.J.D.) and Pennington Biomedical Research Center, Baton Rouge, Louisiana (T.W.G.)

Brain tryptophan concentrations are increased by various stressful treatments, an effect that can be prevented by -adrenoceptor antagonists. This study aimed to determine the -adrenergic subtype responsible for the tryptophan response. Male CD-1 mice received intraperitoneal injections of nonselective and subtype-selective -adrenergic antagonists 20 min before subtype-selective -agonists. Selected brain regions were dissected for analysis of tryptophan content by high-performance liquid chromatography with electrochemical detection. The ₂-selective agonist clenbuterol (0.3 mg/kg) induced increases in brain tryptophan that reached a peak (~60%) 1 h following injection and small but statistically significant increases (~20%) in 5-hydroxyindoleacetic acid: serotonin ratios 2 h following injection. The ₁-selective agonist dobutamine (10 mg/kg) produced less robust increases (~40%) in brain tryptophan, whereas the 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 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 _1/2-selective antagonist propranolol (2.5 mg/kg), the 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 _1/2/3-antagonist bupranolol (10 mg/kg) attenuated it. CL 316243 had no effect on brain tryptophan in ₃-receptor knockout mice, whereas clenbuterol increased brain tryptophan, indicating that -adrenergic modulation of brain tryptophan occurs in the absence of ₃-receptors. We conclude that activation of either ₂- or ₃-adrenergic receptors, but not ₁-adrenergic receptors, increases mouse brain tryptophan content.