title: Genetic dissection of alpha2-adrenoceptor functions in adrenergic versus nonadrenergic cells.
abstract: Alpha(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 alpha(2)-adrenoceptors on adrenergic neurons or alpha(2)-adrenoceptors on nonadrenergic neurons mediate the physiological and pharmacological responses of alpha(2)-agonists, we used the dopamine beta-hydroxylase (Dbh) promoter to drive expression of alpha(2A)-adrenoceptors exclusively in noradrenergic and adrenergic cells of transgenic mice. Dbh-alpha(2A) transgenic mice were crossed with double knockout mice lacking both alpha(2A)- and alpha(2C)-receptors to generate lines with selective expression of alpha(2A)-autoreceptors in adrenergic cells. These mice were subjected to a comprehensive phenotype analysis and compared with wild-type mice, which express alpha(2A)- and alpha(2C)-receptors in both adrenergic and nonadrenergic cells, and alpha(2A)/alpha(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 alpha(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 alpha(2)-receptors in nonadrenergic cells. In dopamine beta-hydroxylase knockout mice lacking norepinephrine, the alpha(2)-agonist medetomidine still induced a loss of the righting reflex, confirming that the sedative effect of alpha(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 alpha(2)-adrenergic receptors, and it provides important new considerations for future drug development.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Freiburg, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gilsbach
authors.forename: Christoph
authors.initials: C
authors.lastname: Röser
authors.forename: Nadine
authors.initials: N
authors.lastname: Beetz
authors.forename: Marc
authors.initials: M
authors.lastname: Brede
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hadamek
authors.forename: Miriam
authors.initials: M
authors.lastname: Haubold
authors.forename: Jost
authors.initials: J
authors.lastname: Leemhuis
authors.forename: Melanie
authors.initials: M
authors.lastname: Philipp
authors.forename: Johanna
authors.initials: J
authors.lastname: Schneider
authors.forename: Michal
authors.initials: M
authors.lastname: Urbanski
authors.forename: Bela
authors.initials: B
authors.lastname: Szabo
authors.forename: David
authors.initials: D
authors.lastname: Weinshenker
authors.forename: Lutz
authors.initials: L
authors.lastname: Hein
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D006993:Hypnotics and Sedatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D018341:Receptors, Adrenergic, alpha-2 / Q000235:genetics / Q000502:physiology*; D019076:Transgenes
chemical_list: D000316:Adrenergic alpha-Agonists; D000700:Analgesics; D000777:Anesthetics; D006993:Hypnotics and Sedatives; D018341:Receptors, Adrenergic, alpha-2; D009638:Norepinephrine