Noradrenaline is necessary for the hedonic properties of addictive drugs.
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.
Jasmin
Luc
L
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
Narasaiah
Mena
M
Tien
Duc
D
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
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