title: Noradrenaline is necessary for the hedonic properties of addictive drugs.
abstract: To determine whether noradrenaline (NA) is an essential neurotransmitter for addictive and appetitive behaviors, we measured drug and food seeking in transgenic mice lacking dopamine beta-hydroxylase (Dbh), the enzyme responsible for synthesizing NA. Using the conditioned place preference test (CPP), we show that Dbh -/- mice do not exhibit rewarding behavior to morphine, cocaine, or the mixed reuptake inhibitor bupropion. In spite of their lack of preference for drugs, Dbh -/- mice had an unaltered preference for food. Drug seeking was induced when NA was restored to the central nervous system of Dbh -/- mice by administration of l-threo-3,4-dihydroxyphenylserine (DOPS) and carbidopa. When a NK1 receptor antagonist was co-administered with morphine or cocaine, it produced aversive behavior in Dbh -/- mice while it abolished place preference in the controls. NK1 antagonists alone did not have any rewarding or aversive effect in the CPP suggesting that substance P opposes some of the unpleasant effects of morphine and cocaine. Our results show that NAergic transmission is necessary for motivated behaviors, the dysregulation of which is a co-morbid factor of many depressive states. The reversibility of this phenomenon, by restoring NA, indicates that even when this behavioral deficit is genetically determined it can be reversed.
authors.affiliation: Department of Neurological Surgery and W.M. Keck Foundation Center for Integrative Neuroscience, University of California San Francisco, San Francisco, CA 94143, USA. ucpain@itsa.ucsf.edu
authors.forename: Luc
authors.initials: L
authors.lastname: Jasmin
authors.forename: Mena
authors.initials: M
authors.lastname: Narasaiah
authors.forename: Duc
authors.initials: D
authors.lastname: Tien
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D001070:Appetitive Behavior / Q000187:drug effects / Q000502:physiology*; D001552:Benzazepines / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D016642:Bupropion / Q000494:pharmacology; D002230:Carbidopa / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004299:Dopamine beta-Hydroxylase / Q000172:deficiency / Q000235:genetics; D015103:Droxidopa / Q000494:pharmacology; D005260:Female; D005838:Genotype; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D009271:Naltrexone / Q000494:pharmacology; D009292:Narcotic Antagonists; D064729:Neurokinin-1 Receptor Antagonists; D009638:Norepinephrine / Q000378:metabolism / Q000502:physiology*; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors; D012201:Reward; D019966:Substance-Related Disorders / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control
chemical_list: C547717:Adra1b protein, mouse; D058668:Adrenergic alpha-1 Receptor Antagonists; D001552:Benzazepines; D001713:Biphenyl Compounds; D018765:Dopamine Uptake Inhibitors; D009292:Narcotic Antagonists; D064729:Neurokinin-1 Receptor Antagonists; D018340:Receptors, Adrenergic, alpha-1; D017447:Receptors, Dopamine D1; D016642:Bupropion; D009271:Naltrexone; D009020:Morphine; D004299:Dopamine beta-Hydroxylase; D003042:Cocaine; D015103:Droxidopa; D002230:Carbidopa; C066892:CP 96345; D009638:Norepinephrine