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Simultaneous absence of dopamine D1 and D2 receptor-mediated signaling is lethal in mice

Kobayashi, Minoru and Iaccarino, Ciro and Saiardi, Adolfo and Heidt, Valérie and Bozzi, Yuri and Picetti, Roberto and Vitale, Carmine and Westphal, Heiner and Drago, John and Borrelli, Emiliana (2004) Simultaneous absence of dopamine D1 and D2 receptor-mediated signaling is lethal in mice. Proceedings of The National Academy of Sciences, Vol. 101 (31), p. 11465-11470. eISSN 1091-6490. Article.

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DOI: 10.1073/pnas.0402028101

Abstract

Dopamine (DA) controls a wide variety of physiological functions in the central nervous system as well as in the neuroendocrine and gastrointestinal systems. DA signaling is mediated by five cloned receptors named D1-D5. Knockout mouse models for the five receptors have been generated, and, albeit impaired for some important DA-mediated functions, they are viable and can reproduce. D1 and D2 receptors are the most abundant and widely expressed DA receptors. Cooperative/synergistic effects mediated by these receptors have been suggested, in particular, in the control of motor behaviors. To analyze the extent of such interrelationship, we have generated double D1/D2 receptor mutants. Interestingly, in contrast to single knockouts, we found that concurrent ablation of the D1 and D2 receptors is lethal during the second or third week after birth. This dramatic phenotype is likely to be related to altered feeding behavior and dysfunction of the gastrointestinal system, especially because major anatomical changes were not identified in the brain. Similarly, in the absence of functional D1, heterozygous D2 mutants (D1r -/-;D2r +/-) showed severe growth retardation and did not survive their postweaning period. The analysis of motor behavior in D1r/D2r compound mutants showed that loss of D2-mediated functions reduces motor abilities, whereas the effect of D1r ablation on locomotion strongly depends on the experimental paradigms used. These studies highlight the interrelationship between D1 and D2 receptor-mediated control of motor activity, food intake, and gastrointestinal functions, which has been elusive in the single-gene ablation studies.

Item Type:Article
ID Code:3953
Status:Published
Refereed:Yes
Uncontrolled Keywords:Knockout mice, motor function, feeding behavior, gastrointestinal system
Subjects:Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Divisions:001 Università di Sassari > 01 Dipartimenti > Scienze fisiologiche, biochimiche e cellulari
Publisher:The National Academy of Sciences of the USA
eISSN:1091-6490
Publisher Policy:Depositato per gentile concessione dell'Editore. È vietato duplicare e postare il PDF. E' consentito l'uso a solo scopo di studio e di ricerca.
Deposited On:25 May 2010 16:56

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