Neuronal and behavioural abnormalities in striatal function in DARPP-32-mutant mice.
We investigated the role of the protein phosphatase inhibitor, dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), in the expression of striatal neuropeptides and in biochemical and behavioural responses to repeated 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 increased levels of DeltaFosB, a Fos family transcription factor, in the striatum 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 activity in the mutant and wild-type mice, but the mutants showed a higher rate of locomotor sensitization to repeated cocaine exposures. These data show that DARPP-32 is involved in regulating substance P expression in the striatonigral pathway, and in biochemical and behavioural plasticity with chronic administration of cocaine.
Hiroi
N
N
Laboratory of Molecular Psychiatry, Center for Genes and Behaviour, Yale University School of Medicine, New Haven, CT 06508, USA.
Fienberg
A A
AA
Haile
C N
CN
Alburges
M
M
Hanson
G R
GR
Greengard
P
P
Nestler
E J
EJ
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D003042:Cocaine / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000503:physiopathology; D003342:Corpus Striatum / Q000503:physiopathology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004791:Enzyme Inhibitors / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000737:chemistry / Q000502:physiology*; D010750:Phosphoproteins / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000032:analysis
D018765:Dopamine Uptake Inhibitors; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D016760:Proto-Oncogene Proteins c-fos; D003042:Cocaine