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The Journal of Neuroscience, November 1, 2002, 22(21):9150-9154

BRIEF COMMUNICATION
D-Amphetamine Fails to Increase Extracellular Dopamine Levels in Mice Lacking 1b-Adrenergic Receptors: Relationship between Functional and Nonfunctional Dopamine Release

Agnès Auclair¹, Susanna Cotecchia², Jacques Glowinski¹, 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, and ² Institut de Pharmacologie et de Toxicologie, CH-1005 Lausanne, Switzerland

It was found recently that locomotor and rewarding effects of psychostimulants and opiates were dramatically decreased or suppressed in mice lacking 1b-adrenergic receptors [1b-adrenergic receptor knock-outs (1bAR-KOs)] (Drouin et al., 2002). Here we show that blunted locomotor responses induced by 3 and 6 mg/kg D-amphetamine in 1bAR-KO mice [84 and 74%, respectively, when compared with wild-type (WT) mice] are correlated with an absence of D-amphetamine-induced increase in extracellular dopamine (DA) levels in the nucleus accumbens of 1bAR-KO mice. Moreover, basal extracellular DA levels in the nucleus accumbens are lower in 1bAR-KO than in WT littermates (28%; p < 0.001).

In rats however, prazosin, an 1-adrenergic antagonist, decreases D-amphetamine-induced locomotor hyperactivity without affecting extracellular DA levels in the nucleus accumbens, a finding related to the presence of an important nonfunctional release of DA (Darracq et al., 1998). We show here that local D-amphetamine releases nonfunctional DA with the same affinity but a more than threefold lower amplitude in C57BL6/J mice than in Sprague Dawley rats. Altogether, this suggests that a trans-synaptic mechanism amplifies functional DA into nonfunctional DA release.

Our data confirm the presence of a powerful coupling between noradrenergic and dopaminergic neurons through the stimulation of 1b-adrenergic receptors and indicate that nonfunctional DA release is critical in the interpretation of changes in extracellular DA levels. These results suggest that 1b-adrenergic receptors may be important therapeutic pharmacological targets not only in addiction but also in psychosis because most neuroleptics possess anti-1-adrenergic properties.

Key words: 1b-adrenergic receptor; D-amphetamine; dopamine; microdialysis; rats; mice

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Copyright © 2002 Society for Neuroscience  0270-6474/02/22219150-05$05.00/0

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