Mechanisms of locomotor sensitization to drugs of abuse in a two-injection protocol

Valjent, Emmanuel, Bertran-Gonzalez, Jesus, Aubier, Benjamin, Greengard, Paul, Hervé, Denis and Girault, Jean-Antoine (2010) Mechanisms of locomotor sensitization to drugs of abuse in a two-injection protocol. Neuropsychopharmacology, 35 2: 401-415. doi:10.1038/npp.2009.143

Author Valjent, Emmanuel
Bertran-Gonzalez, Jesus
Aubier, Benjamin
Greengard, Paul
Hervé, Denis
Girault, Jean-Antoine
Title Mechanisms of locomotor sensitization to drugs of abuse in a two-injection protocol
Journal name Neuropsychopharmacology   Check publisher's open access policy
ISSN 0893-133X
Publication date 2010
Year available 2009
Sub-type Article (original research)
DOI 10.1038/npp.2009.143
Open Access Status
Volume 35
Issue 2
Start page 401
End page 415
Total pages 15
Place of publication London United Kingdom
Publisher Nature Publishing Group
Language eng
Formatted 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 65 times in Thomson Reuters Web of Science Article | Citations
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Created: Tue, 29 Jul 2014, 15:03:19 EST by J Bertran Gonzalez on behalf of Clem Jones Centre for Ageing Dementia Research