Neuronal and behavioural abnormalities in striatal function in DARPP-32-mutant mice

We investigated the role of the protein phosphatase inhibitor, dopamine- an d cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), in the expression of striatal neuropeptides and in biochemical and behavioural responses to repe ated cocaine administration, using DARPP-32 knock-out mice. The striatum of DARPP-32-mutant mice showed heightened substance-P-like immunoreactivity, but normal levels of other neuropeptides. Repeated cocaine administration i ncreased levels of Delta FosB, a Fos family transcription factor in the str iatum of wild-type mice, and this increase was abolished in DARPP-32-mutant mice. Cocaine (20 mg/kg) acutely induced the same level of locomotor activ ity in the mutant and wild-type mice, but the mutants showed a higher rate of locomotor sensitization to repeated cocaine exposures. These data show t hat DARPP-32 is involved in regulating substance P expression in the striat onigral pathway, and in biochemical and behavioural plasticity with chronic administration of cocaine.