A high rate of relapse is a defining characteristic of substance use disorder for which few
treatments are available. Exposure to environmental cues associated with previous drug use can elicit
relapse by causing the involuntary retrieval of deeply engrained associative memories that trigger a
strong motivation to seek out drugs. Our lab is focused on identifying and disrupting mechanisms that
support these powerful consolidated memories, with the goal of developing therapeutics. A
particularly promising mechanism is regulation of synaptic dynamics by actin polymerization within
dendritic spines. Emerging evidence indicates that memory is supported by structural and functional
plasticity dendritic spines, for which actin polymerization is critical, and that prior drug use increases both spine and actin
dynamics. Indeed we have found that inhibiting amygdala (AMY) actin polymerization immediately or twenty-four hours
prior to testing disrupted methamphetamine (METH)-associated memories, but not food reward or fear memories.
Furthermore, METH training increased AMY spine density which was reversed by actin depolymerization treatment.
Actin dynamics were also shifted to a more dynamic state by METH training. While promising, actin polymerization
inhibitors are not a viable therapeutic, as a multitude of peripheral process (e.g. cardiac function) rely on dynamic actin.
For this reason, we have shifted our focus upstream of actin polymerization to nonmuscle myosin II. We and others have
demonstrated that myosin IIb imparts a mechanical force that triggers spine actin polymerization in response to synaptic
stimulation. Similar to an actin depolymerizing compound, pre-test inhibition of myosin II ATPase activity in the AMY
produced a rapid and lasting disruption of drug-seeking behavior. While many questions remain, these findings indicate
that myosin II represents a potential therapeutic avenue to target the actin cytoskeleton and disrupt the powerful,
extinction-resistant memories capable of triggering relapse.