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

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/K_IR3 channels mediate most of the GABA_B receptor (GABA_BR)-dependent inhibition of layer 5/6 pyramidal neurons in the mPFC and that repeated cocaine suppresses this pathway. This adaptation was selective for GABA_BR-dependent Girk signaling in layer 5/6 pyramidal neurons of the prelimbic cortex (PrLC) and involved a D_1/5 dopamine receptor- and phosphorylation-dependent internalization of GABA_BR 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 GABA_BR-Girk signaling in layer 5/6 pyramidal neurons of the prelimbic cortex appears to represent an early adaptation critical for promoting addiction-related behavior