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
Bibliographical noteFunding 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.