Selective, Retrieval-Independent Disruption of Methamphetamine-Associated Memory by Actin Depolymerization

Abstract

Background Memories associated with drugs of abuse, such as methamphetamine (METH), increase relapse vulnerability to substance use disorder. There is a growing consensus that memory is supported by structural and functional plasticity driven by F-actin polymerization in postsynaptic dendritic spines at excitatory synapses. However, the mechanisms responsible for the long-term maintenance of memories, after consolidation has occurred, are largely unknown. Methods Conditioned place preference (N=112) and context-induced reinstatement of self-administration (N=19) were used to assess the role of F-actin polymerization and myosin II, a molecular motor that drives memory-promoting dendritic spine actin polymerization, in the maintenance of METH-associated memories and related structural plasticity. Results Memories formed through association with methamphetamine (METH), but not associations with foot shock or food reward, were disrupted by a highly-specific actin cycling inhibitor when infused into the amygdala during the post-consolidation maintenance phase. This selective effect of depolymerization on METH-associated memory was immediate, persistent and did not depend upon retrieval or strength of the association. Inhibition of non-muscle myosin II also resulted in a disruption of METH-associated memory. Conclusions Thus, drug-associated memories appear to be actively maintained by a unique form of cycling F-actin driven by myosin II. This finding provides a potential therapeutic approach for the selective treatment of unwanted memories associated with psychiatric disorders that is both selective and does not rely on retrieval of the memory. The results further suggest that memory maintenance depends upon the preservation of polymerized actin.

Acetyl-L-Carnitine Prevents Methamphetamine-Induced Structural Damage on Endothelial Cells via ILK-Related MMP-9 Activity

“…METH impact on actin filaments was observed in previous studies that reported either actin depolymerization, altered cell shape, local accumulation of condensed actin, or disruption of the F-actin parallel strands, leading to compromised TJ function [14,26,45]. In our study, METH exposure led to a dramatic loss of F-actin integrity concomitant with claudin-5 redistribution and decreased expression.…”

“…Importantly, METH-induced BBB increased permeability was associated with reduction and/or redistribution of TJ proteins [10,13]. There is also evidence that it can interfere with actin structure and arrangement, which also may lead to compromised TJ function [14,26]. Although the molecular mechanisms underlying BBB disruption under METH exposure are not fully characterized, the activation of matrix metalloproteinases (MMPs), commonly involved in remodeling and degradation of the neurovascular matrix components and therefore associated with BBB leakiness, has been reported [4,6,9,27].…”

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…Surprisingly, latrunculin microinjection into the NAcore potentiated cocaine-induced reinstatement, indicating that the increase in F-actin after cocaine withdrawal may be compensatory relative to drug-seeking behavior (Toda et al, 2006(Toda et al, , 2010. In a similar line of research, others found that inhibition of actin cycling in the amygdala selectively disrupted methamphetamine-associated memory in methamphetamine CPP and contextual renewal of methamphetamine seeking (Young et al, 2014).…”

Probing the lithium-response pathway in hiPSCs implicates the phosphoregulatory set-point for a cytoskeletal modulator in bipolar pathogenesis

“…Animal modeling of BPD behavior (to determine the response to lithiumresponse pathway manipulation) was as described previously (37)(38)(39) …”