Effect of Repeated Administration of Clenbuterol on the Regulation of β‐Adrenoceptors in the Central Nervous System of the Rat

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Abstract
The effect of the centrally acting β-adrenoceptor agonist clenbuterol on β-adrenergic responsiveness, β-receptor density and N-protein coupling was studied in the rat cerebral cortex (which contains primarily β1-receptors) and cerebellum (containing mostly β2-receptors). The objective was to determine whether clenbuterol's effect on these variables was similar to that produced by standard antidepressants. When given to rats repeatedly, clenbuterol caused a decrease in β-adrenergic responsiveness in slices from either the cerebral cortex or the cerebellum. The decreased β-responsiveness in the cerebellum was associated with a decrease both in the density of β-receptors and in receptor/N-protein coupling. In the cortex, only reduced receptor/N-protein coupling was observed by in vitro ligand-binding methods. However, when quantitative autoradiography was employed, clenbuterol treatment was found to reduce the binding of [125I]iodopindolol to β2-receptors throughout the brain, whereas binding to β1-receptors was not reduced. The down-regulation of β2-receptors by clenbuterol is due to its acting centrally as a β2-agonist. Although clenbuterol has about an equal affinity for β1-receptors and β2-receptors, no evidence was found for agonist activity of this drug at β1-receptors in the cerebral cortex. The strategies described here should be helpful in investigating important properties of centrally acting β-agonists that might have potential as antidepressants.