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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 48; pp. 19407 - 19412
• Main Authors: Shen, Haowei, Moussawi, Khaled, Zhou, Wenhua, Toda, Shigenobu, Kalivas, Peter W
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 29.11.2011; National Acad Sciences
• Subjects: Amino acids; Analysis of Variance; animal models; Animals; Behavioral neuroscience; Biological Sciences; Biotinylation; Cocaine; cortex; Dendrites - ultrastructure; Dendritic spines; drugs; Electrophysiology; Extinction, Psychological - physiology; Gene expression; Heroin; Heroin Dependence - physiopathology; Long-Term Potentiation - physiology; Microscopy, Confocal; N methyl D aspartate receptors; Neurochemistry; Neurons; Nucleus accumbens; Piperidines; Prefrontal Cortex - physiology; Rats; Rats, Sprague-Dawley; receptors; Receptors, N-Methyl-D-Aspartate - metabolism; Recurrence; Relapse; Rodents; Self Administration; Small interfering RNA; Synapses; Synaptic Transmission - physiology; therapeutics
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1112052108

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.