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Genetic Dissection of ₂-Adrenoceptor Functions in Adrenergic versus Nonadrenergic Cells

Institute of Experimental and Clinical Pharmacology and Toxicology (R.G., N.B., M.H., J.L., J.S., M.U., B.S., L.H.) and Centre for Biological Signaling Studies (N.B., L.H.), University of Freiburg, Freiburg, Germany; Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany (C.R., M.B., K.H.); Institute of Cell Biology, Duke University, Durham, North Carolina (M.P.); and Department of Human Genetics, Emory University, Atlanta, Georgia (D.W.)

₂-Adrenoceptors mediate diverse functions of the sympathetic system and are targets for the treatment of cardiovascular disease, depression, pain, glaucoma, and sympathetic activation during opioid withdrawal. To determine whether ₂-adrenoceptors on adrenergic neurons or ₂-adrenoceptors on nonadrenergic neurons mediate the physiological and pharmacological responses of ₂-agonists, we used the dopamine β-hydroxylase (Dbh) promoter to drive expression of _2A-adrenoceptors exclusively in noradrenergic and adrenergic cells of transgenic mice. Dbh-_2A transgenic mice were crossed with double knockout mice lacking both _2A- and _2C-receptors to generate lines with selective expression of _2A-autoreceptors in adrenergic cells. These mice were subjected to a comprehensive phenotype analysis and compared with wild-type mice, which express _2A- and _2C-receptors in both adrenergic and nonadrenergic cells, and _2A/_2C double-knockout mice, which do not express these receptors in any cell type. We were surprised to find that only a few functions previously ascribed to ₂-adrenoceptors were mediated by receptors on adrenergic neurons, including feedback inhibition of norepinephrine release from sympathetic nerves and spontaneous locomotor activity. Other agonist effects, including analgesia, hypothermia, sedation, and anesthetic-sparing, were mediated by ₂-receptors in nonadrenergic cells. In dopamine β-hydroxylase knockout mice lacking norepinephrine, the ₂-agonist medetomidine still induced a loss of the righting reflex, confirming that the sedative effect of ₂-adrenoceptor stimulation is not mediated via autoreceptor-mediated inhibition of norepinephrine release. The present study paves the way for a revision of the current view of the ₂-adrenergic receptors, and it provides important new considerations for future drug development.

Received for publication January 3, 2009.

Accepted for publication February 27, 2009.

Address correspondence to: Dr. Lutz Hein, Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Albertstrasse 25, 79104 Freiburg, Germany. E-mail: lutz.hein{at}pharmakol.uni-freiburg.de

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