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The Journal of Neuroscience, May 27, 2009, 29(21):6955-6963; doi:10.1523/JNEUROSCI.1329-09.2009

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Behavioral/Systems/Cognitive
Prolonged Withdrawal from Repeated Noncontingent Cocaine Exposure Increases NMDA Receptor Expression and ERK Activity in the Nucleus Accumbens

Johanna Schumann and Rami Yaka

Department of Pharmacology, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel

Correspondence should be addressed to Dr. Rami Yaka, Department of Pharmacology, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem 91120, Israel. Email: yaka{at}md.huji.ac.il

Cocaine-induced changes in glutamatergic synaptic transmission in the ventral tegmental area (VTA) and the nucleus accumbens (NAc) play a key role in cocaine behavioral effects. Activation of ionotropic glutamate receptor NMDA receptor (NMDAR) in the VTA is critical for the development of cocaine psychomotor sensitization. However, the role of NMDAR in the NAc, a brain area critical for the expression of cocaine psychomotor sensitization, remains to be explored. Here, we show that repeated noncontingent cocaine injections increased NAc NMDAR subunits, NR1, NR2A, and NR2B 21 d, but not 1 d, after withdrawal from cocaine. These changes were associated with an increase in the GluR1 subunit of the AMPA receptor. We also found a time-dependent increase in extracellular signal-regulated kinase (ERK) activity which correlated with the increased expression of NMDAR subunits. Furthermore, the increase in GluR1 and ERK activity was blocked after inhibition of NR2B-containing NMDAR during the development of cocaine psychomotor sensitization or when the MEK (mitogen-activated protein/ERK kinase) inhibitor was microinjected into the NAc 21 d after withdrawal from cocaine. Together, these results suggest that the development of cocaine psychomotor sensitization triggers a delayed increase in the expression of NMDAR subunits in the NAc, which in turn enhances the activity of ERK. Enhanced ERK activity drives the increased expression of the GluR1 subunits, which increases the excitability of NAc neurons after prolonged withdrawal from cocaine and results in enduring expression of psychomotor sensitization.

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Received March 19, 2009; revised April 28, 2009; accepted April 29, 2009.

Correspondence should be addressed to Dr. Rami Yaka, Department of Pharmacology, School of Pharmacy, Hebrew University of Jerusalem, Jerusalem 91120, Israel. Email: yaka{at}md.huji.ac.il

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