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Title

In utero exposure to cocaine delays postnatal synaptic maturation of glutamatergic transmission in the VTA.

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Published in Nature Neuroscience. 2011, vol. 14, no. 11, p. 1439-46
Abstract Maternal exposure to cocaine may perturb fetal development and affect synaptic maturation in the offspring. However, the molecular mechanism underlying such changes remains elusive. We focused on the postnatal maturation of glutamatergic transmission onto ventral tegmental area dopamine neurons in the mouse. We found that, during the first postnatal week, transmission was dominated by calcium-permeable AMPA receptors and GluN2B-containing NMDA receptors. Subsequently, mGluR1 receptors drove synaptic insertion of calcium-impermeable AMPA receptors and GluN2A-containing NMDAR. When pregnant mice were exposed to cocaine, this glutamate receptor switch was delayed in offspring as a result of a direct effect of cocaine on the fetal dopamine transporter and impaired mGluR1 function. Finally, positive modulation of mGluR1 in vivo was sufficient to rescue maturation. These data identify the molecular target through which in utero cocaine delays postnatal synaptic maturation, reveal the underlying expression mechanism of this impairment and propose a potential rescue strategy.
Keywords Age FactorsAnesthetics, Local/pharmacologyAnimalsAnimals, NewbornBiophysicsCalcium/metabolismCalcium Channel Blockers/pharmacologyChelating Agents/pharmacologyCocaine/pharmacologyDopamine/metabolism/pharmacologyDopamine Agents/pharmacologyDopamine Plasma Membrane Transport Proteins/geneticsDose-Response Relationship, DrugEgtazic Acid/analogs & derivatives/pharmacologyElectric StimulationEstrenes/pharmacologyExcitatory Amino Acid Agents/pharmacologyExcitatory Postsynaptic Potentials/drug effects/physiologyFemaleGene Expression Regulation, Developmental/drug effectsGlutamic Acid/metabolismMaleMiceMice, Inbred C57BLMice, TransgenicNeurons/drug effects/physiologyNicotinic Antagonists/pharmacologyPatch-Clamp Techniques/methodsPhosphodiesterase Inhibitors/pharmacologyPolyamines/pharmacologyPregnancyPrenatal Exposure Delayed Effects/physiopathologyPyrrolidinones/pharmacologyReceptors, Glutamate/metabolismReceptors, Metabotropic Glutamate/genetics/physiologySynapses/drug effects/physiologySynaptic Transmission/drug effects/physiologyTime FactorsVentral Tegmental Area/cytology/drug effects/growth & development
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PMID: 21964489
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Article (Published version) (1.2 MB) - document accessible for UNIGE members only Limited access to UNIGE
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Research group Mécanismes cellulaires de la dépendance et de l'addiction (520)
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BELLONE, Camilla, MAMELI, Manuel, LUESCHER, Christian. In utero exposure to cocaine delays postnatal synaptic maturation of glutamatergic transmission in the VTA. In: Nature Neuroscience, 2011, vol. 14, n° 11, p. 1439-46. https://archive-ouverte.unige.ch/unige:26934

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Deposited on : 2013-03-25

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