RT Journal Article
SR Electronic
T1 Acute Cocaine Exposure Weakens GABA<sub>B</sub> Receptor-Dependent G-Protein-Gated Inwardly Rectifying K<sup>+</sup> Signaling in Dopamine Neurons of the Ventral Tegmental Area
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 12251
OP 12257
DO 10.1523/JNEUROSCI.0494-11.2011
VO 31
IS 34
A1 Arora, Devinder
A1 Hearing, Matthew
A1 Haluk, Desirae M.
A1 Mirkovic, Kelsey
A1 Fajardo-Serrano, Ana
A1 Wessendorf, Martin W.
A1 Watanabe, Masahiko
A1 Luján, Rafael
A1 Wickman, Kevin
YR 2011
UL http://www.jneurosci.org/content/31/34/12251.abstract
AB 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 GABAB receptor (GABABR) 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 GABABR–Girk signaling was observed following repeated cocaine administration. While total Girk2 and GABABR1 mRNA and protein levels were unaltered by cocaine exposure in VTA DA neurons, the cocaine-induced decrease in GABABR–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 GABABR–Girk signaling, implicating D2/3 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.