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Accumbens D2-MSN hyperactivity drives antipsychotic-induced behavioral supersensitivity
Anna Kruyer1, Jeffrey Parrilla-Carrero1, Courtney Powell1
1Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
Molecular Psychiatry
|August 5, 2021
Summary
Long-term antipsychotic treatment can cause dopamine supersensitivity, leading to motor issues and rebound psychosis. Restoring inhibitory currents in D2-MSNs prevents this, offering a new therapeutic approach.
Area of Science:
- Neuroscience
- Pharmacology
- Psychiatry
Background:
- Antipsychotic-induced dopamine supersensitivity is a significant clinical challenge.
- This condition manifests as motor abnormalities, treatment resistance, and rebound psychosis.
- Current understanding of its mechanisms and preventative strategies is limited.
Purpose of the Study:
- To elucidate the cellular and synaptic mechanisms underlying antipsychotic-induced behavioral supersensitivity.
- To identify potential therapeutic targets for preventing or reversing these adverse effects.
Main Methods:
- Investigated plasticity in D2 receptor-expressing medium spiny neurons (D2-MSNs) in the nucleus accumbens core (NAcore).
- Examined changes in AMPA receptor insertion and D2 receptor-dependent inhibitory postsynaptic currents (IPSCs).
- Utilized chemogenetics to restore IPSCs in D2-MSNs.
Main Results:
- Demonstrated long-lasting synaptic plasticity, including Ca2+-permeable AMPA receptor insertion and loss of D2-MSN IPSCs.
- Identified hyperexcitability in a subpopulation of D2-MSNs (21%) as a key factor.
- Linked this hyperexcitability to locomotor sensitization to cocaine and behaviors associated with treatment resistance and substance use disorder.
Conclusions:
- Antipsychotic-induced supersensitivity results from specific synaptic plasticity changes in NAcore D2-MSNs.
- Restoring IPSCs in D2-MSNs effectively prevents the development of behavioral supersensitivity.
- This finding presents a novel therapeutic strategy for managing adverse effects of antipsychotic treatment.
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