Cortical astrocytes regulate ethanol consumption and intoxication in mice

Astrocytes are fundamental building blocks of the central nervous system. Their dysfunction has been implicated in many psychiatric disorders, including alcohol use disorder, yet our understanding of their functional role in ethanol intoxication and consumption is very limited. Astrocytes regulate b...

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Bibliographic Details
Published in:Neuropsychopharmacology (New York, N.Y.) N.Y.), 2021-02, Vol.46 (3), p.500-508
Main Authors: Erickson, E K, DaCosta, A J, Mason, S C, Blednov, Y A, Mayfield, R D, Harris, R A
Format: Article
Language:English
Subjects:
Adenosine
Adenosine A1 receptors
Alcohol Drinking
Alcohol use
Alcoholism
Animals
Astrocytes
Calcium Signaling
Calcium signalling
Central nervous system
Drinking behavior
Ethanol
Ethanol - toxicity
G protein-coupled receptors
Intoxication
Intracellular signalling
Mental disorders
Mice
Mice, Inbred C57BL
Prefrontal cortex
Receptor mechanisms
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Summary:Astrocytes are fundamental building blocks of the central nervous system. Their dysfunction has been implicated in many psychiatric disorders, including alcohol use disorder, yet our understanding of their functional role in ethanol intoxication and consumption is very limited. Astrocytes regulate behavior through multiple intracellular signaling pathways, including G-protein coupled-receptor (GPCR)-mediated calcium signals. To test the hypothesis that GPCR-induced calcium signaling is also involved in the behavioral effects of ethanol, we expressed astrocyte-specific excitatory DREADDs in the prefrontal cortex (PFC) of mice. Activating G -GPCR signaling in PFC astrocytes increased drinking in ethanol-naïve mice, but not in mice with a history of ethanol drinking. In contrast, reducing calcium signaling with an astrocyte-specific calcium extruder reduced ethanol intake. Cortical astrocyte calcium signaling also altered the acute stimulatory and sedative-hypnotic effects of ethanol. Astrocyte-specific G -DREADD activation increased both the locomotor-activating effects of low dose ethanol and the sedative-hypnotic effects of a high dose, while reduced astrocyte calcium signaling diminished sensitivity to the hypnotic effects. In addition, we found that adenosine A1 receptors were required for astrocyte calcium activation to increase ethanol sedation. These results support integral roles for PFC astrocytes in the behavioral actions of ethanol that are due, at least in part, to adenosine receptor activation.
ISSN:0893-133X
1740-634X
DOI:10.1038/s41386-020-0721-0