Elsevier

Biological Psychiatry

Volume 75, Issue 2, 15 January 2014, Pages 96-104
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2013.07.036Get rights and content

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 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 postconsolidation 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 seem 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.

Section snippets

Animals

Adult male Sprague-Dawley rats (300–350 g; Charles River, Wilmington, Massachusetts) and Thy1-GFP(m) mice (10 weeks) were housed under a 12:12 light/dark cycle, with food and water ad libitum. All procedures were performed in accordance with the Scripps Research Institutional Animal Care and Use Committee. Animals were handled for 3–5 days before behavioral conditioning.

Surgery

Rats and mice received implantation with 26G bilateral stainless steel guide cannulae directed at the BLC, and rats received

Maintenance of METH-Associated Memory Is Supported in the Amygdala by a Dynamic Actin Cytoskeleton

For CPP, animals were trained to associate the rewarding effects of METH with the multi-modal environmental context in which it was administered. Two days after training that produced a lasting memory for the METH-paired context (CS+), rats were given a single intra-BLC infusion of LatA, a highly-specific inhibitor of cycling but not stable actin (60). Fifteen minutes after infusion, METH-associated memory was assessed in the absence of the unconditioned stimulus (US), METH reinforcement (

Discussion

In this study, we demonstrate that METH-associated memory can be disrupted through direct actin depolymerization or myosin II inhibition days to weeks after consolidation, in the absence of retrieval. This rapid and persistent disruption of a memory by targeting cycling F-actin after consolidation was unexpected. We and others have previously demonstrated that learning triggers a brief window of F-actin dynamics, such that depolymerization at the time of training prevents the consolidation of

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