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Annual Review of Pharmacology and Toxicology

Volume 65, 2025

Targeting Neuroplasticity in Substance Use Disorders: Implications for Therapeutics

Abstract

The last two decades have witnessed substantial advances in identifying synaptic plasticity responsible for behavioral changes in animal models of substance use disorder. We have learned the most about cocaine-induced plasticity in the nucleus accumbens and its relationship to cocaine seeking, so that is the focus in this review. Synaptic plasticity pointing to potential therapeutic targets has been identified mainly using two drug self-administration models: extinction-reinstatement and abstinence models. A relationship between cocaine seeking and potentiated AMPAR transmission in nucleus accumbens is indicated by both models. In particular, an atypical subpopulation—Ca2+-permeable or CP-AMPARs—mediates cue-induced seeking that persists even after long periods of abstinence, modeling the persistent vulnerability to relapse that represents a major challenge in treating substance use disorder. We review strategies to reverse CP-AMPAR plasticity; strategies targeting other components of excitatory synapses, including dysregulated glutamate uptake and release; and behavioral interventions that can be augmented by harnessing synaptic plasticity.

Keyword(s): glutamate, nucleus accumbens, psychostimulants, substance use disorder, synaptic plasticity, therapeutic approaches
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/content/journals/10.1146/annurev-pharmtox-061724-080548
2025-01-23
2025-04-07
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/content/journals/10.1146/annurev-pharmtox-061724-080548
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Targeting Neuroplasticity in Substance Use Disorders: Implications for Therapeutics
Annual Review of Pharmacology and Toxicology 65, 259 (2025); https://doi.org/10.1146/annurev-pharmtox-061724-080548
/content/journals/10.1146/annurev-pharmtox-061724-080548
/content/journals/10.1146/annurev-pharmtox-061724-080548
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