title: Nonmuscle myosin IIB as a therapeutic target for the prevention of relapse to methamphetamine use.
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.
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.|Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Young
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.|Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Blouin
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.|Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: S B
authors.initials: SB
authors.lastname: Briggs
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.|Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Daws
authors.affiliation: Drug Metabolism and Pharmacokinetics, Translational Research Institute, The Scripps Research Institute, Jupiter, FL, USA.|Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: L
authors.initials: L
authors.lastname: Lin
authors.affiliation: Drug Metabolism and Pharmacokinetics, Translational Research Institute, The Scripps Research Institute, Jupiter, FL, USA.|Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Cameron
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: G
authors.initials: G
authors.lastname: Rumbaugh
authors.affiliation: Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL, USA.|Department of Neuroscience, The Scripps Research Institute, Jupiter, FL, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Miller
mesh_terms: D019969:Amphetamine-Related Disorders / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002491:Central Nervous System Agents / Q000008:administration & dosage*; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D058999:Drug-Seeking Behavior / Q000187:drug effects / Q000502:physiology; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005239:Fear / Q000187:drug effects / Q000502:physiology; D055785:Gene Knockdown Techniques; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D008694:Methamphetamine / Q000008:administration & dosage*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D024501:Nonmuscle Myosin Type IIB / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D055502:Secondary Prevention; D012646:Self Administration; D013037:Spatial Behavior / Q000187:drug effects / Q000502:physiology
chemical_list: D002491:Central Nervous System Agents; D006576:Heterocyclic Compounds, 4 or More Rings; C472645:blebbistatin; D008694:Methamphetamine; D024501:Nonmuscle Myosin Type IIB