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A synthetic small-molecule Isoxazole-9 protects against methamphetamine relapse

Molecular Psychiatry volume 23, pages 629–638 (2018)Cite this article

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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.

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Acknowledgements

We thank Airee Kim, Ana Mohammad-Zadeh, Phillip Silva and Yanabel Grant for excellent technical assistance. This work was supported by grants from the National Science Foundation (to MHG), National Institute on Drug Abuse (to CDM) and National Institute of Alcoholism and Alcohol Abuse (to CDM and MCS). This is manuscript number 29314 from The Scripps Research Institute.

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Author notes

  1. G F Koob

    Present address: 5Current address: National Institute on Alcoholism and Alcohol Abuse, NIH, Rockville, MD, USA.,

  2. C D Mandyam

    Present address: 6Current address: VA San Diego Healthcare System.,

Authors and Affiliations

  1. Department of Neuroscience, The Scripps Research Institute, La Jolla, CA, USA

    M H Galinato, M J Fannon-Pavlich, J C Sobieraj, M C Staples, S S Somkuwar, A Ghofranian, S Chaing, A I Navarro, A Joea, G F Koob & C D Mandyam

  2. Department of Neuroscience, University of California San Diego, La Jolla, CA, USA

    M H Galinato & C Heyser

  3. 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

    J W Lockner & K D Janda

  4. Department of Molecular and Systems Biology, Dartmouth Geisel School of Medicine, Lebanon, NH, USA

    B W Luikart

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Correspondence to C D Mandyam.

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Galinato, M., Lockner, J., Fannon-Pavlich, M. et al. A synthetic small-molecule Isoxazole-9 protects against methamphetamine relapse. Mol Psychiatry 23, 629–638 (2018). https://doi.org/10.1038/mp.2017.46

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