Clinicians can offer little hope to people addicted to psychostimulants. Recovering addicts are driven to relapse by the motivation and amygdala activation elicited by contextual memory associated with previous drug use and reward. Decades of research largely focused on neurotransmitter systems have failed to yield an effective pharmacotherapy for the treatment of addiction, suggesting the need to investigate novel mechanisms. Strong preliminary data in this proposal indicates that disrupting actin polymerization, the critical regulator of dendritic spine structure, or myosin II, the motor that promotes polymerization, within the amygdala produces a long- lasting disruption of drug seeking induced by contextual memory, without altering other consolidated amygdala-dependent memories. Importantly, this disruption can be made days after training, when the memory has already been stored. Thus, understanding the cell and molecular mechanisms that underlie the vulnerability of these memories may one day result in a novel therapeutic approach to treat relapse, while also advancing understanding of the neurobiology of memory. The central hypothesis driving this proposal is that drug-context associations are supported by structural and functional plasticity in the amygdala. Further, synaptic amygdala actin dynamics may perpetually cycle in response to drug-context pairing, rendering the resulting memories uniquely susceptible to disruption, as cycling actin is inherently stable. Unfortunately, the field knows vey little about how actin dynamics contribute to structural and functional plasticity in the amygdala, or how this is altered by drugs of abuse. This proposal details an innovative approach to understanding how amygdala actin dynamics alter structural and functional plasticity and control drug seeking behavior. A top-down approach will be used to test the hypothesis; moving from manipulations of drug seeking behavior driven by established drug-context associations during self-administration, down to the mechanisms governing plasticity at single dendritic spines in the amygdala (e.g. multiphoton imaging of actin dynamics and structural and functional changes in individual amygdala spines). Importantly, the mechanisms supporting drug-context memories will be compared to those supporting similar contextual memories for food reward. The goals of this project are 3- fold: (1) To determine when context-associated self-administration triggers a shift in amygdala actin dynamics. (2) To determine the impact of spine actin dynamics on amygdala structural and functional plasticity. (3) To determine the relationship between amygdala synaptic plasticity and the stability of a drug-associated memory. It is expected that determining the mechanisms responsible for this striking actin-based disruption of drug seeking will inform the approach to developing novel strategies for substance abuse relapse and the fundamental understanding of amygdala-dependent memory mechanisms, both of which are long-term goals of the laboratory.

Public Health Relevance

The public health relevance of the proposed research is two-fold: (1) The work is expected to identify novel therapeutic targets for the prevention of substance abuse relapse triggered by drug-associated memory that may also be applicable to other forms of aberrant amygdala-dependent memory, such as post-traumatic stress disorder. (2) This work is further expected to profoundly impact our fundamental understanding of the mechanisms governing amygdala plasticity. Taken together, this will significantly contribute to the missions of both NIDA and NIMH.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Satterlee, John S
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Scripps Florida
United States
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Blouin, Ashley M; Pisupati, Swathi; Hoffer, Colton G et al. (2018) Social stress-potentiated methamphetamine seeking. Addict Biol :
Young, Erica J; Briggs, Sherri B; Rumbaugh, Gavin et al. (2017) Nonmuscle myosin II inhibition disrupts methamphetamine-associated memory in females and adolescents. Neurobiol Learn Mem 139:109-116
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