Astrocytes determine conditioned response to morphine via glucocorticoid receptor-dependent regulation of lactate release
Neuropsychopharmacol.. 2019-06-29; 45(2): 404-415
DOI: 10.1038/s41386-019-0450-4
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Skupio U(1), Tertil M(1), Bilecki W(2), Barut J(1), Korostynski M(1), Golda S(1), Kudla L(1), Wiktorowska L(1), Sowa JE(3), Siwiec M(3), Bobula B(3), Pels K(1)(4), Tokarski K(3), Hess G(3), Ruszczycki B(4), Wilczynski G(4), Przewlocki R(5).
Author information:
(1)Department of Molecular Neuropharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
(2)Department of Pharmacology, Laboratory of Pharmacology and Brain Biostructure, Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
(3)Department of Physiology, Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
(4)Department of Neurophysiology, Nencki Institute, Warsaw, Poland.
(5)Department of Molecular Neuropharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
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.
DOI: 10.1038/s41386-019-0450-4
PMID: 31254970