Neuron
Volume 80, Issue 1, 2 October 2013, Pages 159-170
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Article
Repeated Cocaine Weakens GABAB-Girk Signaling in Layer 5/6 Pyramidal Neurons in the Prelimbic Cortex

https://doi.org/10.1016/j.neuron.2013.07.019Get rights and content
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Highlights

  • Girk channels mediate GABABR-induced inhibition of layer 5/6 mPFC pyramidal neurons

  • Cocaine suppresses GABABR-Girk signaling in layer 5/6 mPFC pyramidal neurons

  • The cocaine-induced adaptation is selective and trafficking dependent

  • Persistent suppression of Girk signaling in mPFC presensitizes mice to cocaine

Summary

Repeated cocaine exposure triggers adaptations in layer 5/6 glutamatergic neurons in the medial prefrontal cortex (mPFC) that promote behavioral sensitization and drug-seeking behavior. While suppression of metabotropic inhibitory signaling has been implicated in these behaviors, underlying mechanisms are unknown. Here, we show that Girk/KIR3 channels mediate most of the GABAB receptor (GABABR)-dependent inhibition of layer 5/6 pyramidal neurons in the mPFC and that repeated cocaine suppresses this pathway. This adaptation was selective for GABABR-dependent Girk signaling in layer 5/6 pyramidal neurons of the prelimbic cortex (PrLC) and involved a D1/5 dopamine receptor- and phosphorylation-dependent internalization of GABABR and Girk channels. Persistent suppression of Girk signaling in layer 5/6 of the dorsal mPFC enhanced cocaine-induced locomotor activity and occluded behavioral sensitization. Thus, the cocaine-induced suppression of GABABR-Girk signaling in layer 5/6 pyramidal neurons of the prelimbic cortex appears to represent an early adaptation critical for promoting addiction-related behavior.

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