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Neural activity in striatum has previously been shown to contribute to context-induced reinstatement of heroin, cocaine, and alcohol seeking, but not yet for methamphetamine seeking. In this study, we found that context-induced reinstatement of methamphetamine seeking increased expression of the neural activity marker Fos in dorsal but not ventral striatum. Reversible inactivation of neural activity in dorsolateral but not dorsomedial striatum using the GABA agonists muscimol and baclofen decreased context-induced reinstatement. Based on our previous findings that Fos-expressing neurons play a critical role in conditioned drug effects, we assessed whether context-induced reinstatement was associated with molecular alterations selectively induced within context-activated Fos-expressing neurons. We used fluorescence-activated cell sorting to isolate reinstatement-activated Fos-positive neurons from Fos-negative neurons in dorsal striatum and used quantitative PCR to assess gene expression within these two populations of neurons. Context-induced reinstatement was associated with increased expression of the immediate early genes<jats:italic>Fos<\/jats:italic>and<jats:italic>FosB<\/jats:italic>and the NMDA receptor subunit gene<jats:italic>Grin2a<\/jats:italic>in only Fos-positive neurons. RNAscope<jats:italic>in situ<\/jats:italic>hybridization confirmed that<jats:italic>Grin2a<\/jats:italic>, as well as<jats:italic>Grin2b<\/jats:italic>, expression were increased in only<jats:italic>Fos<\/jats:italic>-positive neurons from dorsolateral, but not dorsomedial, striatum. Our results demonstrate an important role of dorsolateral striatum in context-induced reinstatement of methamphetamine seeking and that this reinstatement is associated with unique gene alterations in Fos-expressing neurons.<\/jats:p>","DOI":"10.1523\/jneurosci.4997-14.2015","type":"journal-article","created":{"date-parts":[[2015,4,8]],"date-time":"2015-04-08T16:35:34Z","timestamp":1428510934000},"page":"5625-5639","source":"Crossref","is-referenced-by-count":85,"title":["Context-Induced Reinstatement of Methamphetamine Seeking Is Associated with Unique Molecular Alterations in Fos-Expressing Dorsolateral Striatum Neurons"],"prefix":"10.1523","volume":"35","author":[{"given":"F. 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