Anxiogenic Effects of Neurosteroid Exposure: Sex Differences and Altered GABAA Receptor Pharmacology in Adult Rats

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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.