Heroin relapse requires long-term potentiation-like plasticity mediated by NMDA2b-containing receptors

Persistent relapse to addictive drugs constitutes the most challenging problem in addiction therapy, and is linked to impaired prefrontal cortex regulation of motivated behaviors involving the nucleus accumbens. Using a rat model of heroin addiction, we show that relapse requires long-term potentiation (LTP)-like increases in synaptic strength in the prefrontal cortex projection to the nucleus accumbens. The increased synaptic strength was paralleled by dendritic spine enlargement in accumbens spiny neurons and required up-regulated surface expression of NMDA2b-containing receptors (NR2B). Accordingly, blocking NR2B before reinstating heroin-seeking prevented the induction of LTP-like changes in spine remodeling and synaptic strength, and inhibited heroin relapse. These data show that LTP-like neuroplasticity in prefrontal-accumbens synapses is initiated by NR2B stimulation and strongly contributes to heroin relapse. Moreover, the data reveal NR2B-containing NMDA receptors as a previously unexplored therapeutic target for treating heroin addiction.

[1]  David A. Richards,et al.  Glutamate induces the rapid formation of spine head protrusions in hippocampal slice cultures , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[2]  S. Hyman,et al.  Neural mechanisms of addiction: the role of reward-related learning and memory. , 2006, Annual review of neuroscience.

[3]  Bryan Kolb,et al.  Structural plasticity associated with exposure to drugs of abuse , 2004, Neuropharmacology.

[4]  J. Rogers,et al.  The neural circuitry underlying reinstatement of heroin-seeking behavior in an animal model of relapse , 2008, Neuroscience.

[5]  A. Kelley.  Memory and Addiction Shared Neural Circuitry and Molecular Mechanisms , 2004, Neuron.

[6]  Paul G. Middlebrooks,et al.  NMDA receptor antagonists reveal age-dependent differences in the properties of visual cortical plasticity. , 2008, Journal of neurophysiology.

[7]  Mark J. Thomas,et al.  Cocaine Experience Controls Bidirectional Synaptic Plasticity in the Nucleus Accumbens , 2007, The Journal of Neuroscience.

[8]  David W. Self,et al.  Extinction-induced upregulation in AMPA receptors reduces cocaine-seeking behaviour , 2003, Nature.

[9]  S. Cull-Candy,et al.  Role of Distinct NMDA Receptor Subtypes at Central Synapses , 2004, Science's STKE.

[10]  D. Winder,et al.  NMDAR LTP and LTD induction: 2B or Not 2B...is that the question? , 2007 .

[11]  C. Papasian,et al.  Stability of surface NMDA receptors controls synaptic and behavioral adaptations to amphetamine , 2009 .

[12]  J. Peters,et al.  Infralimbic Prefrontal Cortex Is Responsible for Inhibiting Cocaine Seeking in Extinguished Rats , 2008, The Journal of Neuroscience.

[13]  K. Svoboda,et al.  Experience-dependent structural synaptic plasticity in the mammalian brain , 2009, Nature Reviews Neuroscience.

[14]  Bernardo L Sabatini,et al.  Anatomical and physiological plasticity of dendritic spines. , 2007, Annual review of neuroscience.

[15]  Y. Shaham,et al.  Differential Effects of Blockade of Dopamine D1-Family Receptors in Nucleus Accumbens Core or Shell on Reinstatement of Heroin Seeking Induced by Contextual and Discrete Cues , 2007, The Journal of Neuroscience.

[16]  C. Ferrario,et al.  AMPA receptor plasticity in the nucleus accumbens after repeated exposure to cocaine , 2010, Neuroscience & Biobehavioral Reviews.

[17]  F. Leri,et al.  Inactivation of the ventromedial prefrontal cortex mimics re-emergence of heroin seeking caused by heroin reconditioning , 2008, Neuroscience Letters.

[18]  Y. Shaham,et al.  Activation of Group II Metabotropic Glutamate Receptors in the Nucleus Accumbens Shell Attenuates Context-Induced Relapse to Heroin Seeking , 2006, Neuropsychopharmacology.

[19]  M. Diana,et al.  Morphine withdrawal‐induced morphological changes in the nucleus accumbens , 2005, The European journal of neuroscience.

[20]  Brian R. Lee,et al.  A Silent Synapse-Based Mechanism for Cocaine-Induced Locomotor Sensitization , 2011, The Journal of Neuroscience.

[21]  Brian R. Lee,et al.  In Vivo Cocaine Experience Generates Silent Synapses , 2009, Neuron.

[22]  J. Poncer.  Hippocampal long term potentiation: silent synapses and beyond , 2003, Journal of Physiology-Paris.

[23]  R. LaLumiere,et al.  Glutamate Release in the Nucleus Accumbens Core Is Necessary for Heroin Seeking , 2008, The Journal of Neuroscience.

[24]  P. Kalivas,et al.  Prefrontal Glutamate Release into the Core of the Nucleus Accumbens Mediates Cocaine-Induced Reinstatement of Drug-Seeking Behavior , 2003, The Journal of Neuroscience.

[25]  Mriganka Sur,et al.  Effects of synaptic activity on dendritic spine motility of developing cortical layer v pyramidal neurons. , 2006, Cerebral cortex.

[26]  M. Bear,et al.  LTP and LTD An Embarrassment of Riches , 2004, Neuron.

[27]  A. Auerbach,et al.  Reaction mechanism determines NMDA receptor response to repetitive stimulation , 2004, Nature.

[28]  P. Kalivas,et al.  Altered Dendritic Spine Plasticity in Cocaine-Withdrawn Rats , 2009, The Journal of Neuroscience.

[29]  R. Gainetdinov,et al.  Local Knockdown of Genes in the Brain Using Small Interfering RNA: A Phenotypic Comparison with Knockout Animals , 2007, Biological Psychiatry.

[30]  M. Wolf.  The Bermuda Triangle of cocaine-induced neuroadaptations , 2010, Trends in Neurosciences.

[31]  JaneR . Taylor,et al.  Targeting extinction and reconsolidation mechanisms to combat the impact of drug cues on addiction , 2009, Neuropharmacology.

[32]  P. Kalivas.  The glutamate homeostasis hypothesis of addiction , 2009, Nature Reviews Neuroscience.

[33]  Takahisa Taguchi,et al.  Diminished Neuronal Activity Increases Neuron-Neuron Connectivity Underlying Silent Synapse Formation and the Rapid Conversion of Silent to Functional Synapses , 2005, The Journal of Neuroscience.

[34]  K. Berridge.  Faculty Opinions recommendation of Review. Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction. , 2008 .

[35]  Alison L. Barth,et al.  NMDAR EPSC kinetics do not regulate the critical period for LTP at thalamocortical synapses , 2001, Nature Neuroscience.

[36]  M. Foster Olive,et al.  N-Acetylcysteine Reverses Cocaine Induced Metaplasticity , 2009, Nature Neuroscience.

[37]  Kuei Yuan Tseng,et al.  Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving , 2008, Nature.

[38]  R. Malenka,et al.  Synaptic plasticity and addiction , 2007, Nature Reviews Neuroscience.

[39]  T. Robinson,et al.  Widespread but regionally specific effects of experimenter‐ versus self‐administered morphine on dendritic spines in the nucleus accumbens, hippocampus, and neocortex of adult rats , 2002, Synapse.

[40]  T. Robbins,et al.  Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction , 2008, Philosophical Transactions of the Royal Society B: Biological Sciences.

[41]  Karel Svoboda,et al.  NMDA Receptor Subunit-Dependent [Ca2+] Signaling in Individual Hippocampal Dendritic Spines , 2005, The Journal of Neuroscience.