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- W2583931277 abstract "Cocaine addiction is a chronic, unremitting brain disorder. In a rodent extinction-reinstatement model of cocaine self-administration (SA), the ability of drug-paired cues to precipitate relapse to drug-seeking requires stimulation of dopamine receptors in the prefrontal cortex (PFC) and activation of glutamatergic transmission in the PFC to the nucleus accumbens core pathway. Here, we tested the hypothesis that spike frequency adaptation (i.e., accommodation) in PFC neurons is regulated via a dopamine-mediated closure of inhibitory voltage-gated potassium channels KCNQ/Kv7 and chronic cocaine-SA causes an enduring overactivation of this mechanism. To investigate this, we prepared brain slices from animals with a history of chronic cocaine-SA, extinction training or cue-reinstatement testing and recorded glutamatergic pyramidal cells (L5) in the current clamp and voltage clamp configurations. At 24-hours after completion of operant training, all sampled cells in tissue from control (yoked-saline and yoked-cocaine) rats displayed accommodation. In contrast, in tissue from cocaine-SA rats at 24-hours after completion of operant training, 84% of cells lacked accommodation. This neuroadaptation was enduring and evident following 14d of extinction (60% cells) or re-exposure to drug predictive cues (75% cells). In similar experiments in slices from transgenic cFos-GFP rats, the adaptation was correlated with induction of cFos. In control (but not cocaine-SA) tissue, bath applied dopamine (10 micromolar) inhibited both accommodation and IKCNQ, with no further reduction in response bath application of the KCNQ channel antagonist XE-991. Furthermore, pharmacological stabilization of KCNQ channels with retigabine restored IKCNQ in slices from cocaine-SA rats and attenuated cue-induced reinstatement when microinjected into the PFC. Thus, dopamine mediated changes in inhibitory KCNQ channels may contribute to PFC hyperexcitability following cocaine-SA." @default.
- W2583931277 created "2017-02-10" @default.
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- W2583931277 date "2017-02-01" @default.
- W2583931277 modified "2023-09-28" @default.
- W2583931277 title "Chronic Cocaine Self-Administration Potentiates the Dopamine-Induced Hyperexcitability Gated by Inhibition of KCNQ/Kv7 Channels" @default.
- W2583931277 doi "https://doi.org/10.1016/j.bpj.2016.11.2384" @default.
- W2583931277 hasPublicationYear "2017" @default.
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