Alpha1b-adrenergic receptors control locomotor and rewarding effects of psychostimulants and opiates.
Drugs of abuse, such as psychostimulants and opiates, are generally considered as exerting their locomotor and rewarding effects through an increased dopaminergic transmission in the nucleus accumbens. Noradrenergic transmission may also be implicated because most psychostimulants increase norepinephrine (NE) release, and numerous studies have indicated interactions between noradrenergic and dopaminergic neurons through alpha1-adrenergic receptors. However, analysis of the effects of psychostimulants after either destruction of noradrenergic neurons or pharmacological blockade of alpha1-adrenergic receptors led to conflicting results. Here we show that the locomotor hyperactivities induced by d-amphetamine (1-3 mg/kg), cocaine (5-20 mg/kg), or morphine (5-10 mg/kg) in mice lacking the alpha1b subtype of adrenergic receptors were dramatically decreased when compared with wild-type littermates. Moreover, behavioral sensitizations induced by d-amphetamine (1-2 mg/kg), cocaine (5-15 mg/kg), or morphine (7.5 mg/kg) were also decreased in knock-out mice when compared with wild-type. Ruling out a neurological deficit in knock-out mice, both strains reacted similarly to novelty, to intraperitoneal saline, or to the administration of scopolamine (1 mg/kg), an anti-muscarinic agent. Finally, rewarding properties could not be observed in knock-out mice in an oral preference test (cocaine and morphine) and conditioned place preference (morphine) paradigm. Because catecholamine tissue levels, autoradiography of D1 and D2 dopaminergic receptors, and of dopamine reuptake sites and locomotor response to a D1 agonist showed that basal dopaminergic transmission was similar in knock-out and wild-type mice, our data indicate a critical role of alpha1b-adrenergic receptors and noradrenergic transmission in the vulnerability to addiction.
Drouin
Candice
C
Institut National de la Santé et de la Recherche Médicale U.114, Collège de France.
Darracq
Laurent
L
Trovero
Fabrice
F
Blanc
Gérard
G
Glowinski
Jacques
J
Cotecchia
Susanna
S
Tassin
Jean-Pol
JP
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000317:Adrenergic alpha-Antagonists / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D002755:Choice Behavior / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology; D003433:Crosses, Genetic; D003913:Dextroamphetamine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D011224:Prazosin / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D012201:Reward; D019966:Substance-Related Disorders / Q000209:etiology / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology
C547717:Adra1b protein, mouse; D000317:Adrenergic alpha-Antagonists; D000697:Central Nervous System Stimulants; D018491:Dopamine Agonists; D018727:Muscarinic Antagonists; D009294:Narcotics; D018340:Receptors, Adrenergic, alpha-1; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D015102:3,4-Dihydroxyphenylacetic Acid; D009020:Morphine; D003042:Cocaine; D003913:Dextroamphetamine; D004298:Dopamine; D009638:Norepinephrine; D011224:Prazosin