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The Journal of Neuroscience, April 1, 2002, 22(7):2873-2884

alpha 1b-Adrenergic Receptors Control Locomotor and Rewarding Effects of Psychostimulants and Opiates

Candice Drouin1, Laurent Darracq1, Fabrice Trovero2, Gérard Blanc1, Jacques Glowinski1, Susanna Cotecchia3, and Jean-Pol Tassin1

1 Institut National de la Santé et de la Recherche Médicale U.114, Collège de France, 75231 Paris, Cedex 05, France, 2 KEY-OBS, S.A. Centre d'innovation, 45074 Orléans, Cedex 2, France, and 3 Institut de Pharmacologie et de Toxicologie, CH-1005 Lausanne, Switzerland

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 alpha 1-adrenergic receptors. However, analysis of the effects of psychostimulants after either destruction of noradrenergic neurons or pharmacological blockade of alpha 1-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 alpha 1b 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 alpha 1b-adrenergic receptors and noradrenergic transmission in the vulnerability to addiction.

Key words: alpha 1b-adrenergic receptors; knock-out mice; locomotor activity; D-amphetamine; cocaine; morphine; behavioral sensitization; oral test; CPP

Copyright © 2002 Society for Neuroscience  0270-6474/02/2272873-12$05.00/0


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