ArticleMolecular psychiatry2020
Cocaine engages a non-canonical, dopamine-independent, mechanism that controls neuronal excitability in the nucleus accumbens.
Article in Molecular psychiatry, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 27 citations in OpenAlex.
- Transcriptional regulation of ventral hippocampus-nucleus accumbens circuit excitability drives cocaine seeking.Science advances · 2026Article
- Fundamental sex differences in cocaine-induced plasticity of D1R- and D2R-MSNs in the mouse nucleus accumbens core.Biology of sex differences · 2025Article
- Comprehensive Analysis of Age- and Sex-Related Expression of the Chaperone Protein Sigma-1R in the Mouse Brain.Brain sciences · 2024Article
- Fundamental Sex Differences in Cocaine-Induced Plasticity of Dopamine D1 Receptor- and D2 Receptor-Expressing Medium Spiny Neurons in the Mouse Nucleus Accumbens Shell.Biological psychiatry global open science · 2024Article
- Single cocaine exposure attenuates the intrinsic excitability of CRH neurons in the ventral BNST via Sigma-1 receptors.Translational neuroscience · 2024Article
- Membrane excitability of nucleus accumbens neurons gates the incubation of cocaine craving.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2023Article
- Gut colonization by Proteobacteria alters host metabolism and modulates cocaine neurobehavioral responses.Cell host & microbe · 2022Article
- Sigma-1 Receptor in Retina: Neuroprotective Effects and Potential Mechanisms.International journal of molecular sciences · 2022Review
- Cocaine restricts nucleus accumbens feedforward drive through a monoamine-independent mechanism.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2022Article
- Repeated inhibition of sigma-1 receptor suppresses GABAFrontiers in molecular neuroscience · 2022Article
- Revisiting the sigma-1 receptor as a biological target to treat affective and cognitive disorders.Neuroscience and biobehavioral reviews · 2022Review
- Sigma-1 Receptor (S1R) Interaction with Cholesterol: Mechanisms of S1R Activation and Its Role in Neurodegenerative Diseases.International journal of molecular sciences · 2021Article
- Sigma-1 receptor ablation impedes adipocyte-like differentiation of mouse embryonic fibroblasts.Cellular signalling · 2020Article
- Caveolin-1 regulates medium spiny neuron structural and functional plasticity.Psychopharmacology · 2020Article
- The sigma-1 receptor behaves as an atypical auxiliary subunit to modulate the functional characteristics of Kv1.2 channels expressed in HEK293 cells.Physiological reports · 2019Article
- The Sigma-1 Receptor: When Adaptive Regulation of Cell Electrical Activity Contributes to Stimulant Addiction and Cancer.Frontiers in neuroscience · 2019Review
- Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases.Frontiers in neuroscience · 2019Review
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.