Abstract
A single exposure to psychostimulants or morphine is sufficient to induce persistent locomotor sensitization, as well as neurochemical and electrophysiological changes in rodents. Although it provides a unique model to study the bases of long-term behavioral plasticity, sensitization mechanisms remain poorly understood. We investigated in the mouse, a species suited for transgenic studies, the mechanisms of locomotor sensitization showed by the increased response to a second injection of drug (two-injection protocol of sensitization, TIPS). The first cocaine injection induced a locomotor sensitization that was completely context-dependent, increased during the first week, and persisted 3 months later. The induction of sensitized responses to cocaine required dopamine D1 and glutamate NMDA receptors. A single injection of the selective dopamine transporter blocker GBR12783 was sufficient to activate extracellular signal-regulated kinase (ERK) in the striatum to the same level as cocaine and to induce sensitization to cocaine, but not to itself. The induction of sensitization was sensitive to protein synthesis inhibition by anisomycin after cocaine administration. Morphine induced a pronounced context-dependent sensitization that crossed with cocaine. Sensitization to morphine injection was prevented in knockin mutant mice bearing a Thr-34-Ala mutation of DARPP-32, which suppresses its ability to inhibit protein phosphatase-1 (PP1), but not mutation of Thr-75 or Ser-130. These results combined with previous ones show that TIPS in mouse is a context-dependent response, which involves an increase in extracellular dopamine, stimulation of D1 and NMDA receptors, regulation of the cAMP-dependent and ERK pathways, inhibition of PP1, and protein synthesis. It provides a simple and sensitive paradigm to study the mechanisms of long-term effects of drugs of abuse.
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Acknowledgements
The work was funded by INSERM and grants from Fondation pour la Recherche Médicale (FRM) to DH and JAG, and from Agence Nationale de la Recherche to JAG (grants ANR-05-NEUR-020-03 and ANR-BLAN08-1_346422), from National Institute of Drug Abuse (DA10044) to PG, and from Neuropôle de Recherche Francilien (NeRF), Région Ile de France. JBG and BA were supported by FRM. We thank Anne-Gaëlle Corbillé for her help with some experiments and Alice Rousseau and Philippe Bernard for their help with the mutant mice.
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The authors declare that over the past 3 years PG has received compensation from Intracellular Therapies, Inc; PsychoGenics; Neurologix; Pfizer; Sanofi-Aventis. The other authors have no conflict of interest to declare.
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Valjent, E., Bertran-Gonzalez, J., Aubier, B. et al. Mechanisms of Locomotor Sensitization to Drugs of Abuse in a Two-Injection Protocol. Neuropsychopharmacol 35, 401–415 (2010). https://doi.org/10.1038/npp.2009.143
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DOI: https://doi.org/10.1038/npp.2009.143
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