title: A synthetic small-molecule Isoxazole-9 protects against methamphetamine relapse.
abstract: Adult neurogenesis in the dentate gyrus (DG) is strongly influenced by drug-taking behavior and may have a role in the etiology of drug-seeking behavior. However, mechanistic studies on the relationship of neurogenesis on drug seeking are limited. Outbred Wistar rats experienced extended access methamphetamine self-administration and individual differences in drug taking defined animals with higher preferred and lower preferred levels of drug intake. Forced abstinence from higher preferred levels of drug taking enhanced neurogenesis and neuronal activation of granule cell neurons (GCNs) in the DG and produced compulsive-like drug reinstatement. Systemic treatment with the drug Isoxazole-9 (a synthetic small molecule known to modulate neurogenesis in the adult rodent brain) during abstinence blocked compulsive-like context-driven methamphetamine reinstatement. Isoxazole-9 modulated neurogenesis, neuronal activation and structural plasticity of GCNs, and expression of synaptic proteins associated with learning and memory in the DG. These findings identify a subset of newly born GCNs within the DG that could directly contribute to drug-seeking behavior. Taken together, these results support a direct role for the importance of adult neurogenesis during abstinence in compulsive-like drug reinstatement.
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.|Department of Neuroscience, University of California San Diego, La Jolla, CA, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Galinato
authors.affiliation: Departments of Chemistry and Immunology and Microbial Science, The Skaggs Institute for Chemical Biology, and The Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: J W
authors.initials: JW
authors.lastname: Lockner
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Fannon-Pavlich
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Sobieraj
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: M C
authors.initials: MC
authors.lastname: Staples
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: S S
authors.initials: SS
authors.lastname: Somkuwar
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Ghofranian
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chaing
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: A I
authors.initials: AI
authors.lastname: Navarro
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Joea
authors.affiliation: Department of Molecular and Systems Biology, Dartmouth Geisel School of Medicine, Lebanon, NH, USA.
authors.forename: B W
authors.initials: BW
authors.lastname: Luikart
authors.affiliation: Departments of Chemistry and Immunology and Microbial Science, The Skaggs Institute for Chemical Biology, and The Worm Institute of Research and Medicine (WIRM), The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: K D
authors.initials: KD
authors.lastname: Janda
authors.affiliation: Department of Neuroscience, University of California San Diego, La Jolla, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Heyser
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: G F
authors.initials: GF
authors.lastname: Koob
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Mandyam
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects; D018891:Dentate Gyrus / Q000187:drug effects; D058999:Drug-Seeking Behavior / Q000187:drug effects* / Q000502:physiology; D007206:Individuality; D007555:Isoxazoles / Q000494:pharmacology*; D007858:Learning / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D008694:Methamphetamine / Q000009:adverse effects; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012008:Recurrence; D012646:Self Administration; D019966:Substance-Related Disorders / Q000188:drug therapy; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D007555:Isoxazoles; C560085:N-cyclopropyl-5-(thiophen-2-yl)isoxazole-3-carboxamide; D013876:Thiophenes; D008694:Methamphetamine