title: Role of the ventral tegmental area in methamphetamine extinction: AMPA receptor-mediated neuroplasticity.
abstract: The molecular mechanisms underlying drug extinction remain largely unknown, although a role for medial prefrontal cortex (mPFC) glutamate neurons has been suggested. Considering that the mPFC sends glutamate efferents to the ventral tegmental area (VTA), we tested whether the VTA is involved in methamphetamine (METH) extinction via conditioned place preference (CPP). Among various METH-CPP stages, we found that the amount of phospho-GluR1/Ser845 increased in the VTA at behavioral extinction, but not the acquisition or withdrawal stage. Via surface biotinylation, we found that levels of membrane GluR1 were significantly increased during METH-CPP extinction, while no change was observed at the acquisition stage. Specifically, the number of dendritic spines in the VTA was increased at behavioral extinction, but not during acquisition. To validate the role of the mPFC in METH-CPP extinction, we lesioned the mPFC. Ibotenic acid lesioning of the mPFC did not affect METH-CPP acquisition, however, it abolished the extinction stage and reversed the enhanced phospho-GluR1/Ser845 levels as well as increases in VTA dendritic spines during METH-CPP extinction. Overall, this study demonstrates that the mPFC plays a critical role in METH-CPP extinction and identifies the VTA as an alternative target in mediating the extinction of drug conditioning.
authors.affiliation: Department of Physiology and Pharmacology, Institute of Biomedical Sciences, School of Medicine, Chang-Gung University, Tao-Yuan 333, Taiwan.
authors.forename: Han-Ting
authors.initials: HT
authors.lastname: Chen
authors.affiliation: Department of Physiology and Pharmacology, Institute of Biomedical Sciences, School of Medicine, Chang-Gung University, Tao-Yuan 333, Taiwan Healthy Ageing Research Center, Chang-Gung University, Tao-Yuan 333, Taiwan Neuroscience Research Center, Chang-Gung Memorial Hospital, Tao-Yuan 333, Taiwan jinchen@mail.cgu.edu.tw.
authors.forename: Jin-Chung
authors.initials: JC
authors.lastname: Chen
mesh_terms: D000818:Animals; D003213:Conditioning, Psychological / Q000187:drug effects; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology; D005108:Extinction, Psychological / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000502:physiology*; D018091:Receptors, AMPA / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000502:physiology* / Q000648:ultrastructure
chemical_list: D008694:Methamphetamine; D018091:Receptors, AMPA