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


Kobayashi, M; Iaccarino, C; Saiardi, A; Heidt, V; Bozzi, Y; Picetti, R; Vitale, C; Westphal, H; Drago, J; Borrelli, E; (2004) Simultaneous absence of dopamine D1 and D2 receptor-mediated signaling is lethal in mice. Proceedings of the National Academy of Sciences of the United States of America, 101 (31). pp. 11465-70. ISSN 0027-8424 DOI: https://doi.org/10.1073/pnas.0402028101

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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.<br/>

Item Type: Article
Keywords: Animals, Digestive System/physiopathology, Eating, Failure to Thrive/*genetics/*physiopathology, Feeding Behavior, Female, Genes, Lethal, Hypothalamus/physiopathology, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Motor Neurons/physiology, Phenotype, Receptors, Dopamine D1/*genetics/metabolism, Receptors, Dopamine D2/*genetics/metabolism, Signal Transduction/*physiology, Animals, Digestive System, physiopathology, Eating, Failure to Thrive, genetics, physiopathology, Feeding Behavior, Female, Genes, Lethal, Hypothalamus, physiopathology, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Motor Neurons, physiology, Phenotype, Receptors, Dopamine D1, genetics, metabolism, Receptors, Dopamine D2, genetics, metabolism, Signal Transduction, physiology
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Population Health (2012- )
PubMed ID: 15272078
Web of Science ID: 223134400051
URI: http://researchonline.lshtm.ac.uk/id/eprint/2673160

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