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Research ArticleNEUROPHARMACOLOGY

Activation of β2- and β3-Adrenergic Receptors Increases Brain Tryptophan

Natalie R. Lenard, Thomas W. Gettys and Adrian J. Dunn
Journal of Pharmacology and Experimental Therapeutics May 2003, 305 (2) 653-659; DOI: https://doi.org/10.1124/jpet.102.048249
Natalie R. Lenard
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Thomas W. Gettys
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Adrian J. Dunn
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Abstract

Brain tryptophan concentrations are increased by various stressful treatments, an effect that can be prevented by β-adrenoceptor antagonists. This study aimed to determine the β-adrenergic subtype responsible for the tryptophan response. Male CD-1 mice received intraperitoneal injections of nonselective and subtype-selective β-adrenergic antagonists 20 min before subtype-selective β-agonists. Selected brain regions were dissected for analysis of tryptophan content by high-performance liquid chromatography with electrochemical detection. The β2-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 β1-selective agonist dobutamine (10 mg/kg) produced less robust increases (∼40%) in brain tryptophan, whereas the β3-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 β2-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 β1/2-selective antagonist propranolol (2.5 mg/kg), the β3-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 β1/2/3-antagonist bupranolol (10 mg/kg) attenuated it. CL 316243 had no effect on brain tryptophan in β3-receptor knockout mice, whereas clenbuterol increased brain tryptophan, indicating that β-adrenergic modulation of brain tryptophan occurs in the absence of β3-receptors. We conclude that activation of either β2- or β3-adrenergic receptors, but not β1-adrenergic receptors, increases mouse brain tryptophan content.

Footnotes

  • This work was supported in part by National Institutes of Health Grants MH50947 (A.J.D.) and DK53981 (T.W.G.) and U.S. Department of Agriculture NRICGP0100828 (T.W.G.).

  • Portions of this article have been published in abstract form: Lenard N, O'Donnell JM, and Dunn AJ (2000) Clenbuterol-induced elevation of brain tryptophan is not related to its antidepressant effects.Soc Neurosci Abstr26:1768, and Lenard NR and Dunn AJ (2001) β3-Adrenoceptor agonist administration elevates brain tryptophan. Soc Neurosci Abstr27:813.

  • DOI: 10.1124/jpet.102.048249

  • Abbreviations:
    5-HT
    5-hydroxytryptamine, serotonin
    5-HIAA
    5-hydroxyindoleacetic acid
    ANOVA
    analysis of variance
    AR KO
    adrenergic receptor knockout
    HPLC
    high-performance liquid chromatography
    • Received December 16, 2002.
    • Accepted January 15, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 305 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 305, Issue 2
1 May 2003
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Research ArticleNEUROPHARMACOLOGY

Activation of β2- and β3-Adrenergic Receptors Increases Brain Tryptophan

Natalie R. Lenard, Thomas W. Gettys and Adrian J. Dunn
Journal of Pharmacology and Experimental Therapeutics May 1, 2003, 305 (2) 653-659; DOI: https://doi.org/10.1124/jpet.102.048249

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Research ArticleNEUROPHARMACOLOGY

Activation of β2- and β3-Adrenergic Receptors Increases Brain Tryptophan

Natalie R. Lenard, Thomas W. Gettys and Adrian J. Dunn
Journal of Pharmacology and Experimental Therapeutics May 1, 2003, 305 (2) 653-659; DOI: https://doi.org/10.1124/jpet.102.048249
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