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Ethanol abolishes vigilance-dependent astroglia network activation in mice by inhibiting norepinephrine release.

ABSTRACT: Norepinephrine adjusts sensory processing in cortical networks and gates plasticity enabling adaptive behavior. The actions of norepinephrine are profoundly altered by recreational drugs like ethanol, but the consequences of these changes on distinct targets such as astrocytes, which exhibit norepinephrine-dependent Ca²⁺ elevations during vigilance, are not well understood. Using in vivo two-photon imaging, we show that locomotion-induced Ca²⁺ elevations in mouse astroglia are profoundly inhibited by ethanol, an effect that can be reversed by enhancing norepinephrine release. Vigilance-dependent astroglial activation is abolished by deletion of α_1A-adrenergic receptor from astroglia, indicating that norepinephrine acts directly on these ubiquitous glial cells. Ethanol reduces vigilance-dependent Ca²⁺ transients in noradrenergic terminals, but has little effect on astroglial responsiveness to norepinephrine, suggesting that ethanol suppresses their activation by inhibiting norepinephrine release. Since abolition of astroglia Ca²⁺ activation does not affect motor coordination, global suppression of astroglial networks may contribute to the cognitive effects of alcohol intoxication.

SUBMITTER: Ye L

PROVIDER: S-EPMC7710743 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Ethanol abolishes vigilance-dependent astroglia network activation in mice by inhibiting norepinephrine release.

Ye Liang L Orynbayev Murat M Zhu Xiangyu X Lim Eunice Y EY Dereddi Ram R RR Agarwal Amit A Bergles Dwight E DE Bhat Manzoor A MA Paukert Martin M

Nature communications 20201202 1

Norepinephrine adjusts sensory processing in cortical networks and gates plasticity enabling adaptive behavior. The actions of norepinephrine are profoundly altered by recreational drugs like ethanol, but the consequences of these changes on distinct targets such as astrocytes, which exhibit norepinephrine-dependent Ca<sup>2+</sup> elevations during vigilance, are not well understood. Using in vivo two-photon imaging, we show that locomotion-induced Ca<sup>2+</sup> elevations in mouse astroglia ...[more]

PMID: 33268792

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Project description:BackgroundEthanol (EtOH) is known to have excitatory effects on dopamine (DA) release, with moderate-to-high doses (0.5 to 2.5 g/kg) of acute EtOH enhancing DA neuron firing rates in the ventral tegmental area (VTA) and DA levels in the nucleus accumbens (NAc). EtOH has also been shown to reduce DA activity, with moderate doses (1 to 2 g/kg) attenuating electrically evoked release, and higher doses (5 g/kg) decreasing NAc DA levels, demonstrating a biphasic effect of EtOH on DA release. The purpose of the current study was to evaluate EtOH's inhibitory effects on NAc DA terminal release under low- and high-frequency stimulation conditions.MethodsUsing fast-scan cyclic voltammetry in NAc slices from C57BL/6J mice, we examined EtOH's (40 to 160 mM) effects on DA release under several different stimulation parameters, varying frequency (5 to 125 Hz), number of pulses (1 to 10), and stimulation intensity (50 to 350 μA). Additionally, calcium concentrations were manipulated under high-frequency stimulation conditions (20 Hz, 10 pulses, 350 μA) to determine whether EtOH's effects were dependent upon calcium concentration, and by extension, the amount of DA release.ResultsAcute EtOH (40 to 160 mM) inhibited DA release to a greater extent under high-frequency, multiple-pulse stimulation conditions, with increased sensitivity at 5 and 10 pulses and frequencies of 20 Hz or higher. High-frequency, multiple-pulse stimulations also resulted in greater DA release compared with single-pulse release, which was controlled by reducing stimulation intensity. Under reduced DA conditions, high-frequency stimulations still showed increased EtOH sensitivity. Reducing calcium levels also decreased DA release at high-frequency stimulations, but did not affect EtOH sensitivity.ConclusionsEtOH appears to inhibit DA release at NAc terminals under high-frequency stimulation conditions that are similar to release events observed during phasic burst firing in DAergic neurons, suggesting that EtOH may provide inhibition of DA terminals selectively during phasic signaling, while leaving tonic DA terminal activity unaffected.

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Ethanol abolishes vigilance-dependent astroglia network activation in mice by inhibiting norepinephrine release.

Publications

Ethanol abolishes vigilance-dependent astroglia network activation in mice by inhibiting norepinephrine release.

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