title: Context-induced reinstatement of methamphetamine seeking is associated with unique molecular alterations in Fos-expressing dorsolateral striatum neurons.
abstract: Context-induced reinstatement of drug seeking is a well established animal model for assessing the neural mechanisms underlying context-induced drug relapse, a major factor in human drug addiction. 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 Fos and FosB and the NMDA receptor subunit gene Grin2a in only Fos-positive neurons. RNAscope in situ hybridization confirmed that Grin2a, as well as Grin2b, expression were increased in only Fos-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.
authors: Behavioral Neuroscience Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, and.
authors: F Javier
authors: FJ
authors: Rubio
authors: Behavioral Neuroscience Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, and.
authors: Qing-Rong
authors: QR
authors: Liu
authors: Behavioral Neuroscience Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, and.
authors: Xuan
authors: X
authors: Li
authors: Behavioral Neuroscience Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, and.
authors: Fabio C
authors: FC
authors: Cruz
authors: Behavioral Neuroscience Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, and.
authors: Rodrigo M
authors: RM
authors: Leão
authors: Behavioral Neuroscience Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, and.
authors: Brandon L
authors: BL
authors: Warren
authors: Behavioral Neuroscience Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, and.
authors: Sarita
authors: S
authors: Kambhampati
authors: Behavioral Neuroscience Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, and.
authors: Klil R
authors: KR
authors: Babin
authors: Behavioral Neuroscience Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, and.
authors: Kylie B
authors: KB
authors: McPherson
authors: Division of Rheumatology, Johns Hopkins School of Medicine, Baltimore, Maryland 21224.
authors: Raffaello
authors: R
authors: Cimbro
authors: Behavioral Neuroscience Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, and.
authors: Jennifer M
authors: http://orcid.org/0000-0001-5636-4071
authors: JM
authors: Bossert
authors: Behavioral Neuroscience Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, and.
authors: Yavin
authors: http://orcid.org/0000-0002-8242-3319
authors: Y
authors: Shaham
authors: Behavioral Neuroscience Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, and bhope@intra.nida.nih.gov.
authors: Bruce T
authors: BT
authors: Hope
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D003342:Corpus Striatum / Q000166:cytology*; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D005108:Extinction, Psychological; D005434:Flow Cytometry; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D016761:Oncogene Proteins v-fos / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D012054:Reinforcement, Psychology; D012646:Self Administration
chemical_list: D000697:Central Nervous System Stimulants; D008694:Methamphetamine; D009419:Nerve Tissue Proteins; D016761:Oncogene Proteins v-fos; D016194:Receptors, N-Methyl-D-Aspartate; C121001:NR2B NMDA receptor
keywords: extinction; neuroadaptations; neuronal ensembles; renewal; self-administration