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The Actin Cytoskeleton as a Therapeutic Target for the Prevention of Relapse to Methamphetamine Use - PubMed

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The Actin Cytoskeleton as a Therapeutic Target for the Prevention of Relapse to Methamphetamine Use

Erica J Young et al. CNS Neurol Disord Drug Targets. 2015.

Abstract

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.

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Figures

Figure 1
Figure 1

Thy1-GFP(m) expression in dendrites and spine processes of the basolateral amygdala complex imaged at 4× and 40×.

Figure 2
Figure 2

Memory formation is dependent on structural and functional synaptic plasticty. Following learning or LTP induction, NMDA receptor activation initiates actin polymerization, or enlongation, which drives dendritic spine enlargement and stablization.

Figure 3
Figure 3

METH-associated memories are associated with a dynamic actin cytoskeleton during the maintenance phase. Animals underwent Saline or METH CPP training then the ratio of monomeric (G-) and filamentous (F-) actin the BLC was assessed. METH CPP potentiated BLC G-actin compared to F-actin.

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