Phosphorylation of DARPP-32 at Threonine-34 is required for cocaine action.
Mice lacking DARPP-32, a striatal-enriched phosphoprotein, show abnormal behavioral and biochemical responses to cocaine, but the role of individual phosphorylation sites in DARPP-32 in these responses is unknown. We show here that mutation of Thr-34 in DARPP-32 mimicked the behavioral phenotype of the constitutive DARPP-32 knockout in cocaine-induced place conditioning, locomotor activity, and sensitization paradigms. In contrast, mutations of Thr75 did not affect conditioned place preference or the acute locomotor response to cocaine, but DARPP-32 Thr-75 mutants showed no locomotor sensitization in response to repeated cocaine administration. Consistent with these behavioral findings, we found that cocaine regulation of gene expression in striatum, including the acute induction of the immediate early genes c-fos and arc (activity-regulated cytoskeletal-associated gene), was abolished in DARPP-32 Thr-34 mutants, but not in Thr-75 mutants. Similarly, induction of the transcription factor DeltaFosB in the ventral striatum (nucleus accumbens) by chronic cocaine was diminished by the Thr-34, but not the Thr-75, mutation. These findings highlight distinct roles of the Thr-34 and Thr-75 phosphorylation sites of DARPP-32 in mediating short- and long-term behavioral and biochemical actions of cocaine.
Zachariou
Venetia
V
Department of Psychiatry, Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, Dallas, TX 75390-9070, USA.
Sgambato-Faure
Véronique
V
Sasaki
Teresa
T
Svenningsson
Per
P
Berton
Olivier
O
Fienberg
Allen A
AA
Nairn
Angus C
AC
Greengard
Paul
P
Nestler
Eric J
EJ
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics / Q000378:metabolism*; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D009154:Mutation / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D013912:Threonine / Q000378:metabolism*; D014157:Transcription Factors
D000697:Central Nervous System Stimulants; D018765:Dopamine Uptake Inhibitors; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497929:Ppp1r1b protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D014157:Transcription Factors; D013912:Threonine; D003042:Cocaine