Hippocampal GluA1-containing AMPA receptors mediate context-dependent sensitization to morphine

• Published in: The Journal of neuroscience 2011-11, Vol.31 (45), p.16279-16291
• Main Authors: Xia, Yan, Portugal, George S, Fakira, Amanda K, Melyan, Zara, Neve, Rachael, Lee, H Thomas, Russo, Scott J, Liu, Jie, Morón, Jose A
• Format: Article
• Language: English
• Subjects: Alanine - genetics; Analysis of Variance; Animals; Behavior, Animal - drug effects; Carrier Proteins - metabolism; Disks Large Homolog 4 Protein; Dose-Response Relationship, Drug; Excitatory Postsynaptic Potentials - drug effects; Gene Transfer Techniques; Green Fluorescent Proteins - genetics; Guanylate Kinases - metabolism; Hippocampus - drug effects; In Situ Nick-End Labeling - methods; Long-Term Potentiation - drug effects; Male; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Morphine - pharmacology; Morphine Dependence - metabolism; Motor Activity - drug effects; Mutation - genetics; Narcotics - pharmacology; Nuclear Proteins - metabolism; Phosphorylation - drug effects; Protein Transport - drug effects; Random Allocation; Receptors, AMPA - genetics; Receptors, AMPA - metabolism; Serine - genetics; Subcellular Fractions - drug effects; Subcellular Fractions - metabolism
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.3835-11.2011

Glutamatergic systems, including AMPA receptors (AMPARs), are involved in opiate-induced neuronal and behavioral plasticity, although the mechanisms underlying these effects are not fully understood. In the present study, we investigated the effects of repeated morphine administration on AMPAR expression, synaptic plasticity, and context-dependent behavioral sensitization to morphine. We found that morphine treatment produced changes of synaptic AMPAR expression in the hippocampus, a brain area that is critically involved in learning and memory. These changes could be observed 1 week after the treatment, but only when mice developed context-dependent behavioral sensitization to morphine in which morphine treatment was associated with drug administration environment. Context-dependent behavioral sensitization to morphine was also associated with increased basal synaptic transmission and disrupted hippocampal long-term potentiation (LTP), whereas these effects were less robust when morphine administration was not paired with the drug administration environment. Interestingly, some effects may be related to the prior history of morphine exposure in the drug-associated environment, since alterations of AMPAR expression, basal synaptic transmission, and LTP were observed in mice that received a saline challenge 1 week after discontinuation of morphine treatment. Furthermore, we demonstrated that phosphorylation of GluA1 AMPAR subunit plays a critical role in the acquisition and expression of context-dependent behavioral sensitization, as this behavior is blocked by a viral vector that disrupts GluA1 phosphorylation. These data provide evidence that glutamatergic signaling in the hippocampus plays an important role in context-dependent sensitization to morphine and supports further investigation of glutamate-based strategies for treating opiate addiction.