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

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 30 days 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.

A self‐organized actomyosin drives multiple intercellular junction disruption and directly promotes neutrophil recruitment in lipopolysaccharide‐induced acute lung injury

“…Mice were euthanized by cervical dislocation under anesthesia, and the blood and lungs were collected 1, 3, 5, and 7 d after LPS application. LatA (0.5 mg/kg) (14), BLEB (5 mg/kg) (15), Y27632 (5 mg/kg) (16), ML-7 (2 mg/kg) (17), and Tb4 protein (10 mg/kg) (18) were intraperitoneally injected twice daily after LPS administration. CD11b neutralizing antibody (100 mg) (19) was reconstituted in sterile PBS and injected through the tail vein once daily after LPS treatment.…”

Methamphetamine learning induces persistent nonmuscle myosin II-dependent spine motility in the basolateral amygdala

“…NMII inhibition disrupts METH-associated memory and reverses BLA spine density with equal efficacy to direct actin depolymerization via Latrunculin A (19,(29)(30)(31). If the persistent BLA spine motility changes observed here are connected to the memory disruption, we would predict that the motility is NMII-dependent.…”

“…We next assessed BLA spine motility following METH-associated learning as a measure of spine actin dynamics. We have previously demonstrated that METH-associated memory is vulnerable to disruption by Blebb days after training in adult and adolescent (P28-35) male and female mice (30). In the current study, P28-35 male and female Thy1-GFP(m) mice underwent conditioned place preference (CPP) training with either saline or METH, followed by imaging one to three days later ( Fig.…”

“…Adolescent mice were trained as previously described (30). CPP consisted of two phases, pretesting and training, followed by imaging 1 to 3 days later.…”

“…We have previously demonstrated that NMII bearing the IIB MHC (Myh10) is a major driver of synaptic actin polymerization to promote and stabilize LTP and long-term memory formation in CA1 of the dorsal hippocampus and the BLA (15,28). In addition, through genetic and pharmacologic manipulations we have established that targeting NMII either directly in the BLA or systemically is well-tolerated and recapitulates the METH-associated memory, drug seeking and BLA spine density effects of direct actin depolymerization (29,30).…”