Cocaine engages a non-canonical, dopamine-independent, mechanism that controls neuronal excitability in the nucleus accumbens

• Published in: Molecular psychiatry 2020-03, Vol.25 (3), p.680-691
• Main Authors: Delint-Ramirez, Ilse, Garcia-Oscos, Francisco, Segev, Amir, Kourrich, Saïd
• Format: Article
• Language: English
• Subjects: 631/378; 631/443; 82/80; 9/74; Addictions; Analysis; Animal behavior; Animals; Behavioral Sciences; Biological Psychology; Brain slice preparation; Care and treatment; Cocaine; Cocaine - metabolism; Cocaine - pharmacology; Cocaine-Related Disorders - metabolism; Dopamine; Dopamine - metabolism; Dopamine D1 receptors; Drug self-administration; Drug-Seeking Behavior - drug effects; Excitability; Excitatory Postsynaptic Potentials - drug effects; HEK293 Cells; Humans; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Neurons; Neurons - metabolism; Neurosciences; Nucleus accumbens; Nucleus Accumbens - drug effects; Nucleus Accumbens - metabolism; Penicillin G; Pharmacotherapy; Phenols; Potassium channels (voltage-gated); Psychiatry; Receptors, Dopamine D1 - metabolism; Receptors, Dopamine D2 - metabolism; Self Administration; Site-directed mutagenesis; Spiny neurons; Substance abuse; Substance-Related Disorders - physiopathology
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-018-0092-7

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 ( σ 1) initiates this mechanism. Subsequently, σ 1 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.