RT Journal Article
SR Electronic
T1 Genetic Dissection of α<sub>2</sub>-Adrenoceptor Functions in Adrenergic versus Nonadrenergic Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1160
OP 1170
DO 10.1124/mol.109.054544
VO 75
IS 5
A1 Gilsbach, Ralf
A1 Röser, Christoph
A1 Beetz, Nadine
A1 Brede, Marc
A1 Hadamek, Kerstin
A1 Haubold, Miriam
A1 Leemhuis, Jost
A1 Philipp, Melanie
A1 Schneider, Johanna
A1 Urbanski, Michal
A1 Szabo, Bela
A1 Weinshenker, David
A1 Hein, Lutz
YR 2009
UL http://molpharm.aspetjournals.org/content/75/5/1160.abstract
AB α2-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 α2-adrenoceptors on adrenergic neurons or α2-adrenoceptors on nonadrenergic neurons mediate the physiological and pharmacological responses of α2-agonists, we used the dopamine β-hydroxylase (Dbh) promoter to drive expression of α2A-adrenoceptors exclusively in noradrenergic and adrenergic cells of transgenic mice. Dbh-α2A transgenic mice were crossed with double knockout mice lacking both α2A- and α2C-receptors to generate lines with selective expression of α2A-autoreceptors in adrenergic cells. These mice were subjected to a comprehensive phenotype analysis and compared with wild-type mice, which express α2A- and α2C-receptors in both adrenergic and nonadrenergic cells, and α2A/α2C 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 α2-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 α2-receptors in nonadrenergic cells. In dopamine β-hydroxylase knockout mice lacking norepinephrine, the α2-agonist medetomidine still induced a loss of the righting reflex, confirming that the sedative effect of α2-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 α2-adrenergic receptors, and it provides important new considerations for future drug development. The American Society for Pharmacology and Experimental Therapeutics