title: Suppression of inhibitory G protein signaling in forebrain pyramidal neurons triggers plasticity of glutamatergic neurotransmission in the nucleus accumbens core.
abstract: Cocaine and other drugs of abuse trigger long-lasting adaptations in excitatory and inhibitory neurotransmission in the mesocorticolimbic system, and this plasticity has been implicated in several key facets of drug addiction. For example, glutamatergic neurotransmission mediated by AMPA receptors (AMPAR) is strengthened in medium spiny neurons (MSNs) in the NAc core and shell during withdrawal following repeated in vivo cocaine administration. Repeated cocaine administration also suppresses inhibitory signaling mediated by G protein-gated inwardly rectifying K+(GIRK) channels in pyramidal neurons of the prelimbic cortex, an important source of glutamatergic input to the NAc core that has been implicated in cocaine-seeking and behavioral sensitization. Here, we tested the hypothesis that suppression of GIRK channel activity in forebrain pyramidal neurons can promote plasticity of glutamatergic signaling in MSNs. Using novel conditional knockout mouse lines, we report that GIRK channel ablation in forebrain pyramidal neurons is sufficient to enhance AMPAR-dependent neurotransmission in D1R-expressing MSNs in the NAc core, while also increasing motor-stimulatory responses to cocaine administration. A similar increase in AMPAR-dependent signaling was seen in both D1R- and D2R-expressing MSNs in the NAc core during withdrawal from repeated cocaine administration in normal mice. Collectively, these data are consistent with the premise that the cocaine-induced suppression of GIRK-dependent signaling in glutamatergic inputs to the NAc core contributes to some of the electrophysiological and behavioral hallmarks associated with repeated cocaine administration.
authors.affiliation: Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, United States.
authors.forename: Ezequiel
authors.initials: E
authors.lastname: Marron Fernandez de Velasco
authors.affiliation: Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, United States.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Carlblom
authors.affiliation: Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, United States.
authors.forename: Zhilian
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, United States. Electronic address: wickm002@umn.edu.
authors.forename: Kevin
authors.initials: K
authors.lastname: Wickman
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology; D059290:Dopaminergic Neurons / Q000502:physiology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D018698:Glutamic Acid / Q000502:physiology*; D008124:Locomotion / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000502:physiology*; D009714:Nucleus Accumbens / Q000378:metabolism / Q000502:physiology*; D016548:Prosencephalon / Q000502:physiology; D017966:Pyramidal Cells / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*
chemical_list: D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D018698:Glutamic Acid; D003042:Cocaine
keywords: AMPA receptor; Cocaine; Kir3; Mice; Nucleus accumbens; Plasticity; Prelimbic cortex