title: Acute cocaine exposure weakens GABA(B) receptor-dependent G-protein-gated inwardly rectifying K+ signaling in dopamine neurons of the ventral tegmental area.
abstract: Enhanced glutamatergic neurotransmission in dopamine (DA) neurons of the ventral tegmental area (VTA), triggered by a single cocaine injection, represents an early adaptation linked to the more enduring effects of abused drugs that characterize addiction. Here, we examined the impact of in vivo cocaine exposure on metabotropic inhibitory signaling involving G-protein-gated inwardly rectifying K(+) (Girk) channels in VTA DA neurons. Somatodendritic Girk currents evoked by the GABA(B) receptor (GABA(B)R) agonist baclofen were diminished in a dose-dependent manner in mice given a single cocaine injection. This adaptation persisted for 3-4 d, was specific for DA neurons of the VTA, and occurred in parallel with an increase in spontaneous glutamatergic neurotransmission. No additional suppression of GABA(B)R-Girk signaling was observed following repeated cocaine administration. While total Girk2 and GABA(B)R1 mRNA and protein levels were unaltered by cocaine exposure in VTA DA neurons, the cocaine-induced decrease in GABA(B)R-Girk signaling correlated with a reduction in Girk2-containing channels at the plasma membrane in VTA DA neurons. Systemic pretreatment with sulpiride, but not SCH23390 (7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol), prevented the cocaine-induced suppression of GABA(B)R-Girk signaling, implicating D(2/3) DA receptor activation in this adaptation. The acute cocaine-induced weakening of somatodendritic Girk signaling complements the previously demonstrated cocaine-induced strengthening of glutamatergic neurotransmission, likely contributing to enhanced output of VTA DA neurons during the early stages of addiction.
authors.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Devinder
authors.initials: D
authors.lastname: Arora
authors.forename: Matthew
authors.initials: M
authors.lastname: Hearing
authors.forename: Desirae M
authors.initials: DM
authors.lastname: Haluk
authors.forename: Kelsey
authors.initials: K
authors.lastname: Mirkovic
authors.forename: Ana
authors.initials: A
authors.lastname: Fajardo-Serrano
authors.forename: Martin W
authors.initials: MW
authors.lastname: Wessendorf
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Rafael
authors.initials: R
authors.lastname: Luján
authors.forename: Kevin
authors.initials: K
authors.lastname: Wickman
mesh_terms: D000818:Animals; D003042:Cocaine / Q000633:toxicity*; D004195:Disease Models, Animal; D004298:Dopamine / Q000502:physiology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004334:Drug Administration Schedule; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D018080:Receptors, GABA-B / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology
chemical_list: D018765:Dopamine Uptake Inhibitors; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D018080:Receptors, GABA-B; D003042:Cocaine; D004298:Dopamine