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

Abstract

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 highperformance liquid chromatography with electrochemical detection. The ␤ 2 -selective agonist clenbuterol (0.3 mg/kg) induced increases in brain tryptophan that reached a peak (ϳ60%) 1 h following injection and small but statistically significant increases (ϳ20%) in 5-hydroxyindoleacetic acid: serotonin ratios 2 h following injection. The ␤ 1 -selective agonist dobutamine (10 mg/kg) produced less robust increases (ϳ40%) in brain tryptophan, whereas the ␤ 3 -selective agonists BRL 37344resulted in larger increases (80 to 100%). Pretreatment with the-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.A wide variety of stressors can increase brain tryptophan content and subsequently affect serotonin (5-HT) metabolism (Curzon et al., 1972;Chaouloff et al., 1985;Dunn, 1988a). Stress-related elevations in brain tryptophan are normal in adrenalectomized animals (Curzon et al., 1972;Dunn and Welch, 1991), but can be blocked by ganglionic blockers and ␤-adrenergic antagonists (Dunn and Welch, 1991), suggesting that the changes are a consequence of peripheral sympathetic activation of ␤-adrenergic receptors. Indeed, peripheral administration of the nonselective ␤-adrenergic agonist isoproterenol (Eriksson and Carlsson, 1988) or the ␤ 2 -selective agonist clenbuterol (Edwards et al., 1989) results in comparable increases in brain tryptophan in rats. Likewise, imipramine, which inhibits norepinephrine reuptake, elevates brain tryptophan through a ␤-adrenergic-dependent mechanism, as evidenced by prevention of its effects by propranolol (Edwards and Sorisio, 1988).There are three known subtypes of ␤-adrenergic receptors, ␤ 1 , ␤ 2 , and ␤ 3 , all of which are thought to couple primarily via G s ␣ to adenylyl cylase, leading to an inc...

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