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

Abstract

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.

Selective Ablation of GIRK Channels in Dopamine Neurons Alters Behavioral Effects of Cocaine in Mice

“…Notably, while the activity of GIRK2 DA WT mice increased with each cocaine injection, the activity of GIRK2 DA KO mice plateaued between the first and third injections. These findings suggest that GIRK2 DA KO mice exhibit a 'presensitized' phenotype similar to that induced by genetic suppression of GIRK-dependent signaling in the mPFC (Hearing et al, 2013).…”

“…The many phenotypes and adaptations associated with global Girk2 ablation, however, confound interpretation of these data (Lujan et al, 2014). For example, VTA DA neurons, NAc medium spiny neurons (MSNs), and layer 5/6 medial prefrontal cortex (mPFC) pyramidal neurons from Girk2 -/-mice exhibit elevated AMPA receptor-mediated neurotransmission (Arora et al, 2010;Hearing et al, 2013). The recent availability of mice lacking GIRK2 in DA neurons permits a more precise evaluation of the role of GIRK-dependent signaling in modulating DA neuron excitability and cocaine-induced behaviors (Kotecki et al, 2015).…”

Molecular Pharmacology ofδ-Opioid Receptors

“…Indeed, Kir3 subunits were coimmunoprecipitated from brain membranes with either of these receptors (Lavine et al, 2002;Ciruela et al, 2010). In addition, cocaine or amphetamine administration leads to cointernalization of GABA B and Kir3 subunits in the VTA and prelimbic cortex (Padgett et al, 2012;Hearing et al, 2013), further arguing in favor of an association between receptors and effectors, which supports their joint regulation. Although there is currently no direct evidence of DOPrs physically associating with any effector in the nervous system, the observation that DOPrs and Kir3 subunits cointernalize when transfected onto cortical neurons (Nagi et al, 2015) is reminiscent of the behavior displayed by native GABA B /Kir3 complexes.…”

Mechanisms underlying the activation of G-protein–gated inwardly rectifying K+(GIRK) channels by the novel anxiolytic drug, ML297

“…Alternatively, molecular adaptations occurring secondary to constitutive Girk gene ablation may underlie these seemingly disparate observations. Indeed, enhanced glutamatergic signaling has been documented in multiple neuron populations in Girk1 −/− and Girk2 −/− mice (36,37). The alcohol sensitivity of GIRK channels suggests that they are relevant molecular targets for ethanol (6,7).…”