A Role for Calmodulin-Stimulated Adenylyl Cyclases in Cocaine Sensitization
| Autor: | Zachary S. Scheiner, Daniel R. Storm, Carlos Sindreu, Derek P. DiRocco, Guy C.-K. Chan |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Male
Threonine MAPK/ERK pathway medicine.medical_specialty Motor Activity CREB Medium spiny neuron Ribosomal Protein S6 Kinases 90-kDa Drug Administration Schedule Article Adenylyl cyclase Mice chemistry.chemical_compound Calmodulin Cocaine Dopamine Uptake Inhibitors Internal medicine Serine medicine Animals Extracellular Signal-Regulated MAP Kinases Protein kinase A Sensitization Mice Knockout Analysis of Variance Behavior Animal Dose-Response Relationship Drug biology General Neuroscience CREB-Binding Protein Cyclic AMP-Dependent Protein Kinases Corpus Striatum Up-Regulation Mice Inbred C57BL medicine.anatomical_structure Endocrinology chemistry Mitogen-activated protein kinase biology.protein Calcium Signal transduction Adenylyl Cyclases Signal Transduction |
| Zdroj: | The Journal of Neuroscience. 29:2393-2403 |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | Cocaine sensitization is produced by repeated exposure to the drug and is thought to reflect neuroadaptations that contribute to addiction. Here, we identify the Ca2+/calmodulin-stimulated adenylyl cyclases, type 1 (AC1) and type 8 (AC8), as novel regulators of this behavioral plasticity. We show that, whereas AC1 and AC8 single knock-out mice (AC1−/−andAC8−/−) exhibit Ca2+-stimulated adenylyl cyclase activity in striatal membrane fractions, AC1/8 double-knock-out (DKO) mice do not. Furthermore, DKO mice are acutely supersensitive to low doses of cocaine and fail to display locomotor sensitization after chronic cocaine treatment. Because of the known role for the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase signaling pathway in cocaine-induced behavioral plasticity and its coupling to calcium-stimulated cAMP signaling in the hippocampus, we measured phosphorylated ERK (pERK) levels in the striatum. Under basal conditions, pERK is upregulated in choline acetyltransferase-positive interneurons in DKO mice relative to wild-type (WT) controls. After acute cocaine treatment, pERK signaling is significantly suppressed in medium spiny neurons (MSNs) of DKO mice relative to WT mice. In addition to the lack of striatal ERK activation by acute cocaine, signaling machinery downstream of ERK is uncoupled in DKO mice. We demonstrate that AC1 and AC8 are necessary for the phosphorylation of mitogen and stress-activated kinase-1 (pMSK1) at Ser376 and Thr581 and cAMP response element-binding protein (pCREB) at Ser133 after acute cocaine treatment. Our results demonstrate that the Ca2+-stimulated adenylyl cyclases regulate long-lasting cocaine-induced behavioral plasticity via activation of the ERK/MSK1/CREB signaling pathway in striatonigral MSNs. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|