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

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.

Memory disrupting effects of nonmuscle myosin II inhibition depend on the class of abused drug and brain region

“…Cannula placements for intra-CNS infusions can be found in Supplemental Figure S5. Together, these data suggest that Blebb's ability to immediately disrupt METH-associated memory may be unique to the BLC (Young et al 2014(Young et al , 2015(Young et al , 2016.…”

“…Moreover, when actin depolymerizing agents are delivered to Area CA1 of the hippocampus (CA1), basolateral amygdala complex (lateral and basolateral amygdala; BLC), infralimbic region of the prefrontal cortex (IL, PFC) or nucleus accumbens (NAc) around the time of learning, memory formation fails (Fischer et al 2004;Mantzur et al 2009;Rex et al 2010;Gavin et al 2012;Bi et al 2015). Recently, we reported an unexpected and unique role for F-actin dynamics in the storage of memories associated with the highly addictive stimulant, methamphetamine (METH) (Young et al 2014(Young et al , 2015. Direct actin depolymerization within the BLC produces an immediate and long-lasting disruption of METH-associated memory storage and drug seeking, along with a concomitant loss of dendritic spines, that is both independent of retrieval and selective, having no effect on memories associated with fear or food reward.…”

Tmod2 is a regulator of cocaine responses through control of striatal and cortical excitability, and drug-induced plasticity

“…However, mIPSC frequency is higher in naïve KO neurons than naïve WT neurons, and cocaine exposure increases mIPSC frequency in KO but not WT neurons ( Fig 5D3). Elevated mIPSC frequency 26 in Tmod2 KO could be a neurophysiological homeostatic adaptation to compensate for increased excitability of accumbens shell neurons due to modified intrinsic and excitatory synaptic properties 95 .…”

“…Perturbations in actin-assembly [12][13][14][15][16] , -capping 17,18 , -disassociating 19,20 ,nucleating 21,22 and -ADP/ATP exchange 23 proteins affects synaptic and structural plasticity. Previous studies have implicated actin dysregulation in morphine 24 , cocaine 25 , methamphetamine 26 , alcohol 27 and nicotine 28,29 addiction. Generally, psychostimulant administration correlates with increases in spine numbers, spine complexity, and spine maturity [30][31][32] .…”

The role of nonmuscle myosin II in polydrug memories and memory reconsolidation

“…Actin polymerization is the process of monomeric globular actin (G-actin) growing into complex, filamentous actin (F-actin) structures (Lin et al 2005;Kramar et al 2006), and is required for memory-promoting structural plasticity. F-actin rapidly stabilizes after fear-associated (Fischer et al 2004;Mantzur et al 2009;Rehberg et al 2010;Rex et al 2010b;Gavin et al 2012), but not METH-associated learning (Young et al 2014(Young et al , 2015(Young et al , 2016Briggs et al 2017), as indicated by differential susceptibility to actin depolymerizers, such as Latrunculin A. The sustained actin dynamics that result from METH-associated learning render these memories uniquely susceptible to disruption long after the learning event.…”