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The Journal of Neuroscience, February 25, 2009, 29(8):2393-2403; doi:10.1523/JNEUROSCI.4356-08.2009

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Behavioral/Systems/Cognitive
A Role for Calmodulin-Stimulated Adenylyl Cyclases in Cocaine Sensitization

Derek P. DiRocco,^1 * Zachary S. Scheiner,^1,2 * Carlos Balet Sindreu,¹ Guy C.-K. Chan,¹ and Daniel R. Storm^1,2

¹Department of Pharmacology and ²Program in Neurobiology and Behavior, University of Washington, Seattle, Washington 98195

Correspondence should be addressed to Daniel R. Storm, 1959 NE Pacific Street, Health Sciences Building J681, Box 357750, Seattle, WA 98195. Email: dstorm{at}u.washington.edu

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^–/– and AC8^–/–) 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.

Key words: adenylate cyclase; cocaine; cAMP; sensitization; ERK; MSK1

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Received Sept. 11, 2008; revised Jan. 21, 2009; accepted Jan. 21, 2009.

Correspondence should be addressed to Daniel R. Storm, 1959 NE Pacific Street, Health Sciences Building J681, Box 357750, Seattle, WA 98195. Email: dstorm{at}u.washington.edu

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