Nonmuscle myosin II inhibition disrupts methamphetamine-associated memory in females and adolescents

Neurobiol Learn Mem. 2017 Mar;139:109-116. doi: 10.1016/j.nlm.2017.01.001. Epub 2017 Jan 7.

Abstract

Memories associated with drug use can trigger strong motivation for the drug, which increases relapse vulnerability in substance use disorder (SUD). Currently there are no treatments for relapse to abuse of psychostimulants, such as methamphetamine (METH). We previously reported that storage of memories associated with METH, but not those for fear or food reward, and the concomitant spine density increase are disrupted in a retrieval-independent manner by depolymerizing actin in the basolateral amygdala complex (BLC) of adult male rats and mice. Similar results are achieved in males through intra-BLC or systemic inhibition of nonmuscle myosin II (NMII), a molecular motor that directly drives actin polymerization. Given the substantial differences in physiology between genders, we sought to determine if this immediate and selective disruption of METH-associated memory extends to adult females. A single intra-BLC infusion of the NMII inhibitor Blebbistatin (Blebb) produced a long-lasting disruption of context-induced drug seeking for at least 30days in female rats that mirrored our prior results in males. Furthermore, a single systemic injection of Blebb prior to testing disrupted METH-associated memory and the concomitant increase in BLC spine density in females. Importantly, as in males, the same manipulation had no effect on an auditory fear memory or associated BLC spine density. In addition, we established that the NMII-based disruption of METH-associated memory extends to both male and female adolescents. These findings provide further support that small molecular inhibitors of NMII have strong therapeutic potential for the prevention of relapse to METH abuse triggered by associative memories.

Keywords: Actin; Addiction; Dendritic spine; Drug seeking; Memory; Retrieval; Synapse.

MeSH terms

  • Animals
  • Central Nervous System Stimulants / pharmacology*
  • Dendritic Spines / drug effects*
  • Drug-Seeking Behavior / drug effects
  • Female
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Memory / drug effects*
  • Methamphetamine / pharmacology*
  • Nonmuscle Myosin Type IIA / antagonists & inhibitors*
  • Nonmuscle Myosin Type IIB / antagonists & inhibitors*
  • Rats
  • Reward
  • Self Administration

Substances

  • Central Nervous System Stimulants
  • Heterocyclic Compounds, 4 or More Rings
  • blebbistatin
  • Methamphetamine
  • Nonmuscle Myosin Type IIA
  • Nonmuscle Myosin Type IIB