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, During the three days preceding the experiments, mice were habituated to behavioural apparatus, when applicable, and to injections by daily intraperitoneal saline administration. Animal care was in accordance with ethical guidelines (Declaration of Helsinki and NIH, publication no. 85-23, revised 1985, European Community Guidelines, and French Agriculture and Forestry Ministry guidelines for handling animals, decree 87849, license A 75-05-22) and approved by the local ethical committees, Animals. Male eight-week-old C57BL/6J mice from Elevage Janvier or Japan-SLC were used for in vivo and slice experiments, respectively. Production of knock-in T34A-DARPP-32, vol.41

, 50 mM in 0.1% dimethylsulphoxide) was from Calbiochem. For in vivo experiments, drugs were dissolved in 0.9% NaCl and injected intraperitoneally (i.p.) except morphine, vol.4, p.7

, Rattus norvegicus DARPP-32 cDNA (mouse residue numbering is used throughout) was amplified by PCR with Pfu (Stratagene) and cloned in the XhoI/EcoRI sites of EGFP-N2 (Clontech), and subjected to site-directed mutagenesis

. Stratagene, Constructs were verified by DNA sequencing. CaMKIa-GFP and pRK5-D1R were gifts. Cell culture and transfection. Striatal neurons (180,000 per well) from 14-day embryonic Swiss mice (Janvier) were transfected after seven days in culture 14 with D32-GFP (1 mg) and pRK5-D1R (1 mg) DNA, using Lipofectamine 2000 in OptiMEM serum-free medium. Treatments were done 24 h later, in fresh Neurobasal medium. CHO-K1 cells (American Type Culture Collection) (25,000 cells per 14-mm diameter coverslip) were cultured in Ham's F-12 medium with 10% foetal bovine serum (FBS), DARPP-32-NES proh was constructed by EcoRI/SalI digestion and ligation of a sequence encoding AAEDIAYQLSRSRNITYLPAGQSVLLQLPQ, p.1

, After three rinses in PBS, cells were treated with blocking buffer (3% BSA in PBS except for H3 immunofluorescence: 1% BSA and 1% FBS) for 45 min (2 h for P-Ser 10-H3) at room temperature. Coverslips were incubated overnight at 4 uC in PBS with 1% BSA and DARPP-32 (1:4,000 dilution) and D1R (1:500 dilution) monoclonal antibodies, Triton X-100, 0.1% SDS, protease inhibitor cocktail (Roche) and phosphatase inhibitor cocktail I and II (Calbiochem)

, Sections were rinsed three times in TBS and mounted in Vectashield. Image acquisition and statistical analysis. Image acquisition with sequential laser scanning confocal microscopy (SP2; Leica) was performed at the Institut du Fer à Moulin Imaging Facility. For brain immunofluorescence, two sections were analysed bilaterally and cells were counted in one field for dorsal striatum, NAc shell and core (data points for an animal correspond to four acquisitions per structure). For cultures, data points correspond to a minimum of 15 transfected cells (minimum of two different experiments with three independent transfections). Data were analysed with Prism (GraphPad) software, using parametric or non-parametric statistics as indicated, depending on the normality of the distribution of variables. Behavioural analysis. Locomotor activity was measured in a circular corridor (Imetronic) 13 . Mice were placed in the corridor 30 min before injection for the acute experiments. Locomotor sensitization was induced by a single injection of cocaine or morphine 13,43 . Food self-administration experiments were conducted in operant chambers (Imetronic) with two holes, one being the active hole, indicated by a cue light. Nose-poking in the active hole resulted in delivery of a food pellet (Phymep). The light was switched off for 10 s after the consumption of the food pellet, Upstate) were added overnight at 4 uC in PBS containing 1% BSA and 0.05% Tween 20. Anti-mouse Alexa488-conjugated antibody or anti-mouse Cy3-conjugated antibody (1:400 dilution; Molecular Probes) were added for 1 h at room temperature. Nuclei were counterstained with SYTOX

, During reversal the previously active hole became inactive, and vice versa. When the same criteria as above had been met, mice were subjected to a single 2-h progressive ratio (PR) session in which the requirement to earn a pellet escalated according to the following series, Acquisition criteria were: stable response with less than 20% deviation from the mean of the total number of reinforcers earned in three consecutive sessions (80% stability)