Repeated Cocaine Weakens GABAB-Girk Signaling in Layer 5/6 Pyramidal Neurons in the Prelimbic Cortex

Matthew Hearing, Lydia Kotecki, Ezequiel MarronFernandezdeVelasco, Ana Fajardo-Serrano, Hee Jung Chung, Rafael Luján, Kevin Wickman

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

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 suppressionof Girk signaling in layer 5/6 of the dorsal mPFCenhanced cocaine-induced locomotor activity andoccluded behavioral sensitization. Thus, thecocaine-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

Original languageEnglish (US)
Pages (from-to)159-170
Number of pages12
JournalNeuron
Volume80
Issue number1
DOIs
StatePublished - Oct 2 2013

Bibliographical note

Funding Information:
This work was supported by NIH grants to KW (MH061933, DA011806, DA034696), MH (DA007097), LK (DA007097), and the Spanish Ministry of Science and Innovation BFU2012-38348 and CONSOLIDER-Ingenio CSD2008-0000 (RL). The authors thank Kelsey Mirkovic, Daniele Young, Matt Novitch, and Edward Kim for excellent technical support.

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