Astrocytes determine conditioned response to morphine via glucocorticoid receptor-dependent regulation of lactate release

To date, neurons have been the primary focus of research on the role of glucocorticoids in the regulation of brain function and pathological behaviors, such as addiction. Astrocytes, which are also glucocorticoid-responsive, have been recently implicated in the development of drug abuse, albeit thro...

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Published in:Neuropsychopharmacology (New York, N.Y.) N.Y.), 2020-01, Vol.45 (2), p.404-415
Main Authors: Skupio, Urszula, Tertil, Magdalena, Bilecki, Wiktor, Barut, Justyna, Korostynski, Michal, Golda, Slawomir, Kudla, Lucja, Wiktorowska, Lucja, Sowa, Joanna E, Siwiec, Marcin, Bobula, Bartosz, Pels, Katarzyna, Tokarski, Krzysztof, Hess, Grzegorz, Ruszczycki, Blazej, Wilczynski, Grzegorz, Przewlocki, Ryszard
Format: Article
Language:English
Subjects:
Analgesics, Opioid - pharmacology
Animals
Astrocytes
Astrocytes - drug effects
Astrocytes - metabolism
Behavioral plasticity
Cells, Cultured
Cocaine
Conditioned response
Conditioning (learning)
Conditioning, Psychological - drug effects
Conditioning, Psychological - physiology
Drug abuse
Electrophysiology
Excitability
Gene expression
Glucocorticoids
Lactic acid
Lactic Acid - metabolism
Metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Morphine
Morphine - pharmacology
Narcotics
Nucleus accumbens
Opioids
Pharmacology
Receptors, Glucocorticoid - metabolism
Regulations
Reinforcement
RNA-mediated interference
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Summary:To date, neurons have been the primary focus of research on the role of glucocorticoids in the regulation of brain function and pathological behaviors, such as addiction. Astrocytes, which are also glucocorticoid-responsive, have been recently implicated in the development of drug abuse, albeit through as yet undefined mechanisms. Here, using a spectrum of tools (whole-transcriptome profiling, viral-mediated RNA interference in vitro and in vivo, behavioral pharmacology and electrophysiology), we demonstrate that astrocytes in the nucleus accumbens (NAc) are an important locus of glucocorticoid receptor (GR)-dependent transcriptional changes that regulate rewarding effects of morphine. Specifically, we show that targeted knockdown of the GR in the NAc astrocytes enhanced conditioned responses to morphine, with a concomitant inhibition of morphine-induced neuronal excitability and plasticity. Interestingly, GR knockdown did not influence sensitivity to cocaine. Further analyses revealed GR-dependent regulation of astroglial metabolism. Notably, GR knockdown inhibited induced by glucocorticoids lactate release in astrocytes. Finally, lactate administration outbalanced conditioned responses to morphine in astroglial GR knockdown mice. These findings demonstrate a role of GR-dependent regulation of astrocytic metabolism in the NAc and a key role of GR-expressing astrocytes in opioid reward processing.
ISSN:0893-133X
1740-634X
DOI:10.1038/s41386-019-0450-4