A Silent Synapse-Based Mechanism for Cocaine-Induced Locomotor Sensitization
Open Access
- 1 June 2011
- journal article
- research article
- Published by Society for Neuroscience in Journal of Neuroscience
- Vol. 31 (22), 8163-8174
- https://doi.org/10.1523/jneurosci.0016-11.2011
Abstract
Locomotor sensitization is a common and robust behavioral alteration in rodents whereby following exposure to abused drugs such as cocaine, the animal becomes significantly more hyperactive in response to an acute drug challenge. Here, we further analyzed the role of cocaine-induced silent synapses in the nucleus accumbens (NAc) shell and their contribution to the development of locomotor sensitization. Using a combination of viral vector-mediated genetic manipulations, biochemistry, and electrophysiology in a locomotor sensitization paradigm with repeated, daily, noncontingent cocaine (15 mg/kg) injections, we show that dominant-negative cAMP-element binding protein (CREB) prevents cocaine-induced generation of silent synapses of young (30 d old) rats, whereas constitutively active CREB is sufficient to increase the number of NR2B-containing NMDA receptors (NMDARs) at synapses and to generate silent synapses. We further show that occupancy of CREB at the NR2B promoter increases and is causally related to the increase in synaptic NR2B levels. Blockade of NR2B-containing NMDARs by administration of the NR2B-selective antagonist Ro256981 directly into the NAc, under conditions that inhibit cocaine-induced silent synapses, prevents the development of cocaine-elicited locomotor sensitization. Our data are consistent with a cellular cascade whereby cocaine-induced activation of CREB promotes CREB-dependent transcription of NR2B and synaptic incorporation of NR2B-containing NMDARs, which generates new silent synapses within the NAc. We propose that cocaine-induced activation of CREB and generation of new silent synapses may serve as key cellular events mediating cocaine-induced locomotor sensitization. These findings provide a novel cellular mechanism that may contribute to cocaine-induced behavioral alterations.Keywords
This publication has 83 references indexed in Scilit:
- AMPA receptor plasticity in the nucleus accumbens after repeated exposure to cocaineNeuroscience & Biobehavioral Reviews, 2010
- Synapse-Specific Metaplasticity: To Be Silenced Is Not to Silence 2BNeuron, 2010
- Metaplasticity at Single Glutamatergic SynapsesNeuron, 2010
- Glutamate transmission in addictionNeuropharmacology, 2009
- In Vivo Cocaine Experience Generates Silent SynapsesNeuron, 2009
- Genome-wide Analysis of Chromatin Regulation by Cocaine Reveals a Role for SirtuinsNeuron, 2009
- Rapid Functional Maturation of Nascent Dendritic SpinesNeuron, 2009
- Silent synapses and the emergence of a postsynaptic mechanism for LTPNature Reviews Neuroscience, 2008
- Neuroplasticity in the mesolimbic dopamine system and cocaine addictionBritish Journal of Pharmacology, 2008
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001