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The Journal of Neuroscience, May 3, 2006, 26(18):4956-4960; doi:10.1523/JNEUROSCI.4601-05.2006

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Brief Communications
Plasticity-Associated Gene Krox24/Zif268 Is Required for Long-Lasting Behavioral Effects of Cocaine

Emmanuel Valjent,^1,2,3 Benjamin Aubier,^1,2,3 Anne-Gaëlle Corbillé,^1,2,3 Karen Brami-Cherrier,^1,2,3,4 Jocelyne Caboche,⁴ Piotr Topilko,^5,6 Jean-Antoine Girault,^1,2,3 and Denis Hervé^1,2,3

¹Institut National de la Santé et de la Recherche Médicale (INSERM), Unité 536, F-75005 Paris, France, ²Université Pierre et Marie Curie–Paris 6, F-75005 Paris, France ³Institut du Fer a Moulin, F-75005 Paris, France, ⁴Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7102, F-75005 Paris, France, ⁵INSERM, Unité 368, F-75230 Paris, France, and ⁶Ecole Normale Supérieure, F-75230 Paris, France

Correspondence should be addressed to Dr. Jean-Antoine Girault, Institut National de la Santé et de la Recherche Médicale Unité 536, Institut du Fer à Moulin, 17 rue du Fer à Moulin, 75005 Paris, France. Email: girault{at}fer-a-moulin.inserm.fr

The extracellular signal-regulated kinases (ERKs) 1/2 pathway is stimulated by drugs of abuse in striatal neurons through coincident activation of dopamine D₁ and glutamate NMDA receptors and is critical for long-lasting behavioral effects of these drugs. Although regulation of transcription is a major target of ERK, the precise mechanisms by which it contributes to behavioral alterations is not known. We examined the role of Zif268, an immediate-early gene induced by drugs of abuse under the control of ERK, in behavioral responses to cocaine using knock-in mutant mice in which Zif268 was replaced by LacZ. No biochemical or behavioral differences between mutant and wild-type mice were observed in basal conditions or in acute responses to cocaine injection. In contrast, locomotor sensitization to single or repeated cocaine injections was dramatically diminished in both heterozygous and homozygous Zif268 mutant mice. Conditioned place preference in response to cocaine was prevented in Zif268-deficient mice. This effect was not attributable to a general learning deficit because the mutant mice displayed normal conditioned place preference when food was used as reward. Our results provide direct genetic evidence for the requirement of Zif268 for long-lasting association of environmental context with specific behavioral responses after short exposures to cocaine. They also underline the common molecular machinery involved in long-lasting drug-induced behavioral alterations and the formation of other types of memory.

Key words: mice; Zif268; food; cocaine; sensitization; conditioned place preference

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Received Oct. 27, 2005; revised March 8, 2006; accepted March 28, 2006.

Correspondence should be addressed to Dr. Jean-Antoine Girault, Institut National de la Santé et de la Recherche Médicale Unité 536, Institut du Fer à Moulin, 17 rue du Fer à Moulin, 75005 Paris, France. Email: girault{at}fer-a-moulin.inserm.fr

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