Mechanisms of locomotor sensitization to drugs of abuse in a two-injection protocol.
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.
Valjent
Emmanuel
E
Inserm UMR-S 839, Paris, France.
Bertran-Gonzalez
Jesus
J
Aubier
Benjamin
B
Greengard
Paul
P
Hervé
Denis
D
Girault
Jean-Antoine
JA
D000704:Analysis of Variance; D000818:Animals; D000841:Anisomycin / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics; D004333:Drug Administration Routes; D004334:Drug Administration Schedule; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009020:Morphine / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D009294:Narcotics / Q000494:pharmacology; D017354:Point Mutation / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D020891:Raclopride / Q000494:pharmacology; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000235:genetics; D019966:Substance-Related Disorders / Q000235:genetics / Q000503:physiopathology*; D013912:Threonine / Q000235:genetics; D013997:Time Factors
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D018691:Excitatory Amino Acid Antagonists; D009294:Narcotics; D011500:Protein Synthesis Inhibitors; D017447:Receptors, Dopamine D1; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D013912:Threonine; D020891:Raclopride; D000841:Anisomycin; D016291:Dizocilpine Maleate; D009020:Morphine; D048049:Extracellular Signal-Regulated MAP Kinases; D003042:Cocaine