GIRK Channels Modulate Opioid-Induced Motor Activity in a Cell Type- and Subunit-Dependent Manner
| Autor: | Marco Pravetoni, Kevin Wickman, Nora M. McCall, Lydia Kotecki, Ezequiel Marron Fernandez de Velasco, Nicole C. Victoria, Matthew C. Hearing, Michaelanne B. Munoz, Paul A. Slesinger, C. David Weaver, Zhilian Xia, Devinder Arora |
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| Rok vydání: | 2015 |
| Předmět: |
Cell type
Heteromer Motor Activity Midbrain Mice Dopamine medicine Animals G protein-coupled inwardly-rectifying potassium channel GABAergic Neurons Mice Knockout Dose-Response Relationship Drug urogenital system Chemistry Dopaminergic Neurons General Neuroscience Ventral Tegmental Area Articles Analgesics Opioid Mice Inbred C57BL Ventral tegmental area Protein Subunits medicine.anatomical_structure G Protein-Coupled Inwardly-Rectifying Potassium Channels nervous system Opioid Disinhibition medicine.symptom Neuroscience medicine.drug |
| Zdroj: | The Journal of Neuroscience. 35:7131-7142 |
| ISSN: | 1529-2401 0270-6474 |
| Popis: | G-protein-gated inwardly rectifying K+(GIRK/Kir3) channel activation underlies key physiological effects of opioids, including analgesia and dependence. GIRK channel activation has also been implicated in the opioid-induced inhibition of midbrain GABA neurons and consequent disinhibition of dopamine (DA) neurons in the ventral tegmental area (VTA). Drug-induced disinhibition of VTA DA neurons has been linked to reward-related behaviors and underlies opioid-induced motor activation. Here, we demonstrate that mouse VTA GABA neurons express a GIRK channel formed by GIRK1 and GIRK2 subunits. Nevertheless, neither constitutive genetic ablation ofGirk1orGirk2, nor the selective ablation of GIRK channels in GABA neurons, diminished morphine-induced motor activity in mice. Moreover, direct activation of GIRK channels in midbrain GABA neurons did not enhance motor activity. In contrast, genetic manipulations that selectively enhanced or suppressed GIRK channel function in midbrain DA neurons correlated with decreased and increased sensitivity, respectively, to the motor-stimulatory effect of systemic morphine. Collectively, these data support the contention that the unique GIRK channel subtype in VTA DA neurons, the GIRK2/GIRK3 heteromer, regulates the sensitivity of the mouse mesolimbic DA system to drugs with addictive potential. |
| Databáze: | OpenAIRE |
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