Cell type-specific regulation of DARPP-32 phosphorylation by psychostimulant and antipsychotic drugs.
DARPP-32 is a dual-function protein kinase/phosphatase inhibitor that is involved in striatal signaling. The phosphorylation of DARPP-32 at threonine 34 is essential for mediating the effects of both psychostimulant and antipsychotic drugs; however, these drugs are known to have opposing behavioral and clinical effects. We hypothesized that these drugs exert differential effects on striatonigral and striatopallidal neurons, which comprise distinct output pathways of the basal ganglia. To directly test this idea, we developed bacterial artificial chromosome transgenic mice that allowed the analysis of DARPP-32 phosphorylation selectively in striatonigral and striatopallidal neurons. Using this new methodology, we found that cocaine, a psychostimulant, and haloperidol, a sedation-producing antipsychotic, exert differential effects on DARPP-32 phosphorylation in the two neuronal populations that can explain their opposing behavioral effects. Furthermore, we found that a variety of drugs that target the striatum have cell type-specific effects that previous methods were not able to discern.
Bateup
Helen S
HS
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Ave., New York, New York 10065, USA.
Svenningsson
Per
P
Kuroiwa
Mahomi
M
Gong
Shiaoching
S
Nishi
Akinori
A
Heintz
Nathaniel
N
Greengard
Paul
P
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002110:Caffeine / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D003024:Clozapine / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000187:drug effects / Q000378:metabolism*; D005917:Globus Pallidus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006220:Haloperidol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000145:classification / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000187:drug effects; D013378:Substantia Nigra / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497929:Ppp1r1b protein, mouse; D002110:Caffeine; D003042:Cocaine; D003024:Clozapine; D006220:Haloperidol