There are no pharmacotherapies for stimulant abuse, including methamphetamine (METH) and relapse rates
are high. Relapse triggered by reminders of drug use is a particular challenge to prevent, as the underlying
memories exert a powerful motivational influence over behavior and represent a lifelong relapse risk factor.
Learning is supported by structural plasticity in dendritic spines, driven by training-induced actin polymer-
ization. Memory stability is subsequently achieved by arresting actin dynamics, stabilizing the cytoskeleton. As
a result, memory is impervious to actin depolymerization within minutes of learning. However, prior work in the
lab discovered that the actin cytoskeleton supporting METH memories remains uniquely dynamic in the
amygdala long after training. This enables selective, retrieval-independent disruption of METH-associated
memories and drug seeking with a single administration of an actin depolymerizer. Because actin’s critical
roles in the body limit its therapeutic potential, focus shifted to nonmuscle myosin II (NMII), a direct driver of
learning-stimulated actin polymerization in spines. The effect of NMII inhibition is specific to the amygdala and
METH. Indeed, NMII inhibition has no effect on METH memories when other regions of the drug-memory
neural circuit are targeted and there is no similar retrieval-independent effect on memories for fear, food
reward or other drugs of abuse, including opioids. Genetic and pharmacologic targeting of NMII established it
is a viable therapeutic target and an NIH-funded medication development project for a clinically safe NMII
inhibitor is underway (UH3 NS096833). However, fundamental knowledge needed to understand and further
leverage this specificity is lacking. This will be addressed through the central hypothesis in this new project:
that METH-associated memories are uniquely supported in the amygdala by NMII, leaving those memories
selectively vulnerable to disruption long after learning, even when other associative learning is introduced. The
focus of this application is two-fold: (1) The key mechanistic question regarding the specific requirement of
the amgydala, actin-NMII and METH for selective memory storage disruption will be addressed. For this, the
impact of METH-related neuromodulators (Aim 1), as well as NMII phosphorylation and interacting partners
(Aim 2) will be studied on NMII-dependent BLA synaptic actin dynamics and METH-associated memory, with a
focus on factors that are unique to METH and the BLA. Once identified, the mechanism(s) responsible could
be harnessed to render relapse-inducing memories for other drugs of abuse vulnerable to disruption. (2)
Because most individuals with METH use disorder use multiple substances, including opioids, it is necessary
to determine the impact of polydrug administration on METH memory susceptibility to NMII inhibition.
Preliminary data indicate that METH confers susceptibility to previously impervious opioid associations.
Technically innovative approaches will be employed throughout the project, spanning from single synapse
manipulations in live tissue slices to memory-based self-administration studies.