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Nonmuscle myosin IIB as a therapeutic target for the prevention of relapse to methamphetamine use

Molecular Psychiatry volume 21, pages 615–623 (2016)Cite this article

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Abstract

Memories associated with drug use increase vulnerability to relapse in substance use disorder (SUD), and there are no pharmacotherapies for the prevention of relapse. Previously, we reported a promising finding that storage of memories associated with methamphetamine (METH), but not memories for fear or food reward, is vulnerable to disruption by actin depolymerization in the basolateral amygdala complex (BLC). However, actin is not a viable therapeutic target because of its numerous functions throughout the body. Here we report the discovery of a viable therapeutic target, nonmuscle myosin IIB (NMIIB), a molecular motor that supports memory by directly driving synaptic actin polymerization. A single intra-BLC treatment with Blebbistatin (Blebb), a small-molecule inhibitor of class II myosin isoforms, including NMIIB, produced a long-lasting disruption of context-induced drug seeking (at least 30 days). Further, postconsolidation genetic knockdown of Myh10, the heavy chain of the most highly expressed NMII in the BLC, was sufficient to produce METH-associated memory loss. Blebb was found to be highly brain penetrant. A single systemic injection of the compound selectively disrupted the storage of METH-associated memory and reversed the accompanying increase in BLC spine density. This effect was specific to METH-associated memory, as it had no effect on an auditory fear memory. The effect was also independent of retrieval, as METH-associated memory was disrupted 24 h after a single systemic injection of Blebb delivered in the home cage. Together, these results argue for the further development of small-molecule inhibitors of NMII as potential therapeutics for the prevention of SUD relapse triggered by drug associations.

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Acknowledgements

We thank the Scripps Florida Genomics Core for their assistance with RNA sequencing, the Scripps Florida Behavior Core for providing behavioral equipment, Dr Christine Gall for her helpful comments and Colton Hoffer for technical assistance. This work was supported by grants from the National Institute on Drug Abuse (R01DA034116, R01DA034116S1 and R21DA036376 to CAM), National Institute for Neurological Disorders and Stroke (R01NS064079 to GR) and National Institute for Mental Health (R01MH096847 to GR) and the Brain and Behavior Research Foundation (NARSAD Young Investigator Awards to AMB and SES).

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  1. E J Young, A M Blouin and S B Briggs: The first three authors contributed equally to this work.

Authors and Affiliations

  1. Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA

    E J Young, A M Blouin, S B Briggs, S E Sillivan & C A Miller

  2. Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA

    E J Young, A M Blouin, S B Briggs, S E Sillivan, G Rumbaugh & C A Miller

  3. Drug Metabolism and Pharmacokinetics, Translational Research Institute, The Scripps Research Institute, Jupiter, FL, USA

    L Lin & M D Cameron

  4. Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL, USA

    L Lin & M D Cameron

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Young, E., Blouin, A., Briggs, S. et al. Nonmuscle myosin IIB as a therapeutic target for the prevention of relapse to methamphetamine use. Mol Psychiatry 21, 615–623 (2016). https://doi.org/10.1038/mp.2015.103

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