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- W2805364456 abstract "Drug-induced enhanced dopamine (DA) signaling in the brain is a canonical mechanism that initiates addiction processes. However, indirect evidence suggests that cocaine also triggers non-canonical, DA-independent, mechanisms that contribute to behavioral responses to cocaine, including psychomotor sensitization and cocaine self-administration. Identifying these mechanisms and determining how they are initiated is fundamental to further our understanding of addiction processes. Using physiologically relevant in vitro tractable models, we found that cocaine-induced hypoactivity of nucleus accumbens shell (NAcSh) medium spiny neurons (MSNs), one hallmark of cocaine addiction, is independent of DA signaling. Combining brain slice studies and site-directed mutagenesis in HEK293T cells, we found that cocaine binding to intracellular sigma-1 receptor (σ1) initiates this mechanism. Subsequently, σ1 binds to Kv1.2 potassium channels, followed by accumulation of Kv1.2 in the plasma membrane, thereby depressing NAcSh MSNs firing. This mechanism is specific to D1 receptor-expressing MSNs. Our study uncovers a mechanism for cocaine that bypasses DA signaling and leads to addiction-relevant neuroadaptations, thereby providing combinatorial strategies for treating stimulant abuse." @default.
- W2805364456 created "2018-06-13" @default.
- W2805364456 creator A5041341752 @default.
- W2805364456 creator A5048359456 @default.
- W2805364456 creator A5079351159 @default.
- W2805364456 creator A5084114747 @default.
- W2805364456 date "2018-06-07" @default.
- W2805364456 modified "2023-10-17" @default.
- W2805364456 title "Cocaine engages a non-canonical, dopamine-independent, mechanism that controls neuronal excitability in the nucleus accumbens" @default.
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- W2805364456 doi "https://doi.org/10.1038/s41380-018-0092-7" @default.
- W2805364456 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/7042730" @default.
- W2805364456 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/29880884" @default.
- W2805364456 hasPublicationYear "2018" @default.
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