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The Journal of Neuroscience, November 24, 2004, 24(47):10716-10725; doi:10.1523/JNEUROSCI.1398-04.2004

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Cellular/Molecular
Activation of the cGMP Pathway in Dopaminergic Structures Reduces Cocaine-Induced EGR-1 Expression and Locomotor Activity

Peggy Jouvert,¹ Marie-Odile Revel,¹ Anelise Lazaris,² Dominique Aunis,¹ Keith Langley,¹ and Jean Zwiller¹

¹Institut National de la Santé et de la Recherche Médicale, Unité 575, Centre de Neurochimie, 67084 Strasbourg, France, and ²Unité Mixte de Recherche 7521 Centre National de la Recherche Scientifique, 67000 Strasbourg, France

Nitric oxide (NO) and the C-type natriuretic peptide (CNP) exert their action on brain via the cGMP signaling pathway. NO, by activating soluble guanylyl cyclase, and CNP, by stimulating membrane-bound guanylyl cyclase, cause intracellular increases of cGMP, activating cGMP-dependent protein kinases (PKGs). We show here that injection of CNP into the rat ventral tegmental area strongly reduced cocaine-induced egr-1 expression in the nucleus accumbens in a dose-dependent manner. The effect of CNP was reversed by the previous injection of a selective PKG inhibitor, KT5823. Activation of PKG by 8-bromo-cGMP reduced, like CNP, cocaine-induced gene transcription in dopaminergic structures. To confirm the involvement of PKG, this was overexpressed in either the mesencephalon or the caudate-putamen. Using the polyethyleneimine delivery system, an active protein was expressed by injecting a plasmid vector containing the human PKG-I cDNA. PKG was overexpressed in dopaminergic and GABAergic neurons when the plasmid was injected in the ventral tegmental area, whereas overexpression was observed in medium spiny GABAergic neurons and in both cholinergic and GABAergic interneurons when the PKG vector was injected into the caudate-putamen. Activation of the overexpressed PKG reduced cocaine-induced egr-1 expression in dopaminergic structures and affected behavior (i.e., locomotor activity). These effects were again reversed by previous injection of the selective PKG inhibitor. The current data suggest that NO and the neuropeptide CNP are potential regulators of cocaine-related effects on behavior.

Key words: cGMP-dependent protein kinase; CNP peptide; cocaine; dopaminergic neurotransmission; immediate-early gene egr-1; psychostimulant

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Received Nov 17, 2003; revised October 13, 2004; accepted October 13, 2004.

This article has been cited by other articles:

				V. BASHKATOVA, J. MEUNIER, A. VANIN, and T. MAURICE Nitric Oxide and Oxidative Stress in the Brain of Rats Exposed In Utero to Cocaine. Ann. N.Y. Acad. Sci., August 1, 2006; 1074: 632 - 642. [Abstract] [Full Text] [PDF]

				A. Roy, Y. K. Fung, X. Liu, and K. Pahan Up-regulation of Microglial CD11b Expression by Nitric Oxide J. Biol. Chem., May 26, 2006; 281(21): 14971 - 14980. [Abstract] [Full Text] [PDF]

				S. Brahmachari, Y. K. Fung, and K. Pahan Induction of glial fibrillary acidic protein expression in astrocytes by nitric oxide. J. Neurosci., May 3, 2006; 26(18): 4930 - 4939. [Abstract] [Full Text] [PDF]

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