title: Marked behavioral activation from inhibitory stimulation of locus coeruleus alpha1-adrenoceptors by a full agonist.
abstract: alpha(1)-Adrenoceptors are concentrated in the locus coeruleus (LC) where they appear to regulate various active behaviors but have been difficult to stimulate effectively. The present study examined the behavioral, pharmacological and neural effects of possible stimulation of these receptors with 6-fluoronorepinephrine (6FNE), the only known selective alpha-agonist that has full efficacy at all brain alpha-receptors. Infusion of this compound in the mouse LC was found to produce extreme activation of diverse motivated behaviors of exploration, wheel-running and operant approach responding in different environments consistent with a global behavioral function of the dorsal noradrenergic system. Infusion of selective antagonists of alpha(1)- (terazosin) or alpha(2)- (atipamezole) receptors or of either the partial alpha(1)-agonist, phenylephrine, or full alpha(2)-agonist, dexmedetomidine, indicated that the behavioral effects of 6FNE were due largely due to activation of LC alpha(1)-receptors consistent with the known greater density of alpha(1)- than alpha(2)-adrenoreceptors in the mouse nucleus. Immunohistochemistry of fos in tyrosine hydroxylase-positive LC neurons following IV ventricular infusions indicated that 6FNE markedly depressed whereas terazosin strongly enhanced the apparent functional activity of the nucleus. The changes in fos expression following 6FNE and terazosin were significantly greater than those following dexmedetomidine and atipamezole. It is hypothesized that the alpha(1)-receptors of the mouse LC are strongly activated by 6FNE and serve to potently inhibit its tonic or stress-induced activity which in turn disinhibits prepotent motivated behaviors.
authors.affiliation: Department of Psychiatry, New York University Langone School of Medicine, 550 First Ave, New York, NY 10016, USA. eric.stone@nyumc.org
authors.forename: Eric A
authors.initials: EA
authors.lastname: Stone
authors.forename: Yan
authors.initials: Y
authors.lastname: Lin
authors.forename: Yasmeen
authors.initials: Y
authors.lastname: Sarfraz
authors.forename: David
authors.initials: D
authors.lastname: Quartermain
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D002408:Catheters, Indwelling; D003216:Conditioning, Operant / Q000187:drug effects*; D005106:Exploratory Behavior / Q000187:drug effects*; D005455:Fluorescent Antibody Technique; D008125:Locus Coeruleus / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D009474:Neurons / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D016760:Proto-Oncogene Proteins c-fos; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase