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The Journal of Neuroscience, August 25, 2004, 24(34):7464-7476; doi:10.1523/JNEUROSCI.0612-04.2004

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Behavioral/Systems/Cognitive
L-Type Ca²⁺ Channels Mediate Adaptation of Extracellular Signal-Regulated Kinase 1/2 Phosphorylation in the Ventral Tegmental Area after Chronic Amphetamine Treatment

Anjali Rajadhyaksha,¹ Isabelle Husson,² Shirish S. Satpute,¹ Karsten D. Küppenbender,² J. Q. Ren,² Rejean M. Guerriero,² David G. Standaert,² and Barry E. Kosofsky²

¹NMR Center, Department of Radiology, and ²Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129

L-type Ca²⁺ channels (LTCCs) play an important role in chronic psychostimulant-induced behaviors. However, the Ca²⁺ second messenger pathways activated by LTCCs after acute and recurrent psychostimulant administration that contribute to drug-induced molecular adaptations are poorly understood. Using a chronic amphetamine treatment paradigm in rats, we have examined the role of LTCCs in activating the mitogen-activated protein (MAP) kinase pathway in the ventral tegmental area (VTA), a primary target for the reinforcing properties of psychostimulants. Using immunoblot and immunohistochemical analyses, we find that in chronic saline-treated rats a challenge injection of amphetamine increases phosphorylation of MAP [extracellular signal-regulated kinase 1/2 (ERK1/2)] kinase in the VTA that is independent of LTCCs. However, in chronic amphetamine-treated rats there is no increase in amphetamine-mediated ERK1/2 phosphorylation unless LTCCs are blocked, in which case there is robust phosphorylation in VTA dopamine neurons. Examination of the expression of phosphatases reveals an increase in calcineurin [protein phosphatase 2B (PP2B)] and MAP kinase phosphatase-1 (MKP-1) in the VTA. Using in situ hybridization histochemistry and immunoblot analyses, we further examined the mRNA and protein expression of the LTCC subtypes Ca_v1.2 and Ca_v1.3 in VTA dopamine neurons in drug-naive animals and in rats after chronic amphetamine treatment. We found an increase in Ca_v1.2 mRNA and protein levels, with no change in Ca_v1.3. Together, our results suggest that one aspect of LTCC-induced changes in second messenger pathways after chronic amphetamine exposure involves activation of the MAP kinase phosphatase pathway by upregulation of Ca_v1.2 in VTA dopaminergic neurons.

Key words: amphetamine; L-type Ca²⁺ channels; VTA; ERK1/2 phosphorylation; Ca_v1.2; addiction

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Received Feb 20, 2004; revised June 18, 2004; accepted July 6, 2004.

This article has been cited by other articles:

				E. Valjent, A.-G. Corbille, J. Bertran-Gonzalez, D. Herve, and J.-A. Girault Inhibition of ERK pathway or protein synthesis during reexposure to drugs of abuse erases previously learned place preference PNAS, February 21, 2006; 103(8): 2932 - 2937. [Abstract] [Full Text] [PDF]

				A. M. Rajadhyaksha and B. E. Kosofsky Psychostimulants, L-type Calcium Channels, Kinases, and Phosphatases Neuroscientist, October 1, 2005; 11(5): 494 - 502. [Abstract] [PDF]

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