Striatal Adenosine Signaling Regulates EAAT2 and Astrocytic AQP4 Expression and Alcohol Drinking in Mice

Lee, Moonnoh R.; Ruby, Christina L.; Hinton, David J.; Choi, Sun Hee; Adams, Chelsea A.; Kang, Na Young; Choi, Doo Sup

doi:10.1038/npp.2012.198

Cited by 56 publications

(57 citation statements)

References 46 publications

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“…Per2 mRNA and protein deficits in ENT1 KO mice are intriguing in light of the resemblance ENT1 KO mice bear to Per2 mutants. Both are well-established animal models of glutamatergic dysregulation and compromised astrocyte function in AUD (Choi et al, 2004;Lee et al, 2013;Nam et al, 2011;Spanagel et al, 2005). Early awakening in ENT1 KO mice is also consistent with the role of Per2 in circadian phase regulation (Albrecht et al, 2001).…”

Section: Discussionsupporting

confidence: 59%

Adenosinergic Regulation of Striatal Clock Gene Expression and Ethanol Intake During Constant Light

Ruby

Vadnie

Hinton

et al. 2014

Neuropsychopharmacol

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Circadian rhythm and sleep disruptions occur frequently in individuals with alcohol use disorders (AUD) and present significant barriers to treatment. Recently, a variant of adenosine transporter, equilibrative nucleoside transporter 1 (ENT1), was associated with the cooccurrence of sleep problems and AUD. We have previously shown that mice lacking ENT1 (ENT1 KO) have reduced adenosine levels in the striatum and drink more alcohol compared with wild types (WT). However, it is unknown whether ENT1 deletion disrupts circadian rhythms, which may contribute to alcohol preference in ENT1 KO mice. Here we used these mice to determine whether endogenous adenosine regulates circadian genetic and behavioral rhythms and influences alcohol intake during chronodisruption. We examined circadian locomotor activity in ENT1 KO vs WT littermates and found that ENT1 KO mice were both active earlier and hyperactive compared with WT mice at night. We used real-time PCR and immunohistochemistry to estimate striatal clock gene levels and found that PER2 expression in the striatum was blunted by ENT1 deletion or A2A receptor (A2AR) antagonism. Next, we exposed ENT1 KO and WT mice to constant light (LL) and found further elevation in ethanol intake in ENT1 KO, but not in WT mice, supporting the notion that circadian dysfunction may contribute to increased alcohol intake in ENT1 KO mice. Finally, we showed that A2AR agonist administration normalized PER1 and PER2 expression and circadian locomotor activity in ENT1 KO mice. Together, our results demonstrate that adenosine signaling regulates cellular and behavioral circadian timing and influences alcohol intake during chronodisruption.

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Section: Discussionsupporting

confidence: 59%

Adenosinergic Regulation of Striatal Clock Gene Expression and Ethanol Intake During Constant Light

Ruby

Vadnie

Hinton

et al. 2014

Neuropsychopharmacol

Self Cite

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“…Deletion or knockdown of ENT1, an adenosine transporter, leads to reduced expression of GLT-1 and an astrocyte-specific water channel, AQP4. Treatment with the β-lactam antibiotic ceftriaxone, a potent inducer of glutamate uptake in astrocytes, increases GLT-1 expression and decreases ethanol drinking in mice, an effect dependent on AQP4 expression [79]. Ceftriaxone blocks glutamate increases in the extracellular space and increases glutamine synthetase activity in the nucleus accumbens [77].…”

Section: Cell-type Specificitymentioning

confidence: 99%

The Neuroimmune Transcriptome and Alcohol Dependence: Potential for Targeted Therapies

et al. 2016

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Transcriptome profiling enables discovery of gene networks that are altered in alcoholic brains. This technique has revealed involvement of the brain's neuroimmune system in regulating alcohol abuse and dependence, and has provided potential therapeutic targets. In this review, we discuss Toll-like-receptor pathways, hypothesized to be key players in many stages of the alcohol addiction cycle. The growing appreciation of the neuroimmune system's involvement in alcoholism has also led to consideration of crucial roles for glial cells, including astrocytes and microglia, in the brain's response to alcohol abuse. We discuss current knowledge and hypotheses on the roles that specific neuroimmune cell types may play in addiction. Current strategies for repurposing US FDA-approved drugs for the treatment of alcohol use disorders are also discussed.

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“…In addition to binding to TrkB, BDNF, like other neurotrophins, can also interact, albeit with lower affinity, with the p75 neurotrophin receptor (p75NTR), a member of the tumor necrosis factor receptor superfamily (Dechant and Barde, 2002;Kraemer et al, 2014a). Interestingly, activation of TrkB and p75NTR produce opposite outcomes Kraemer et al, 2014a).…”

Section: Introductionmentioning

confidence: 99%

The Neurotrophic Factor Receptor p75 in the Rat Dorsolateral Striatum Drives Excessive Alcohol Drinking

et al. 2016

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Brain-derived neurotrophic factor (BDNF) signaling in the dorsolateral striatum (DLS) keeps alcohol intake in moderation. For example, activation of the BDNF receptor tropomyosin receptor kinase B (TrkB) in the DLS reduces intake in rats that consume moderate amounts of alcohol. Here, we tested whether long-term excessive consumption of alcohol produces neuroadaptations in BDNF signaling in the rat DLS. We found that BDNF was no longer able to gate alcohol self-administration after a history of repeated cycles of binge alcohol drinking and withdrawal. We then elucidated the possible neuroadaptations that could block the ability of BDNF to keep consumption of alcohol in moderation. We report that intermittent access to 20% alcohol in a two-bottle choice paradigm that models excessive alcohol drinking produces a mobilization of DLS p75 neurotrophin receptor (p75NTR), whose activities oppose those of the Trk receptors, including TrkB. These neuroadaptations were not observed in the DLS of rats exposed to continuous access to 10% alcohol or in rats consuming sucrose. Furthermore, short hairpin RNA (shRNA)-mediated knockdown of the p75NTR gene in the DLS, as well as intra-DLS infusion or systemic administration of the p75NTR modulator, LM11A-31, significantly reduced binge drinking of alcohol. Together, our results suggest that excessive alcohol consumption produces a change in BDNF signaling in the DLS, which is mediated by the recruitment of p75NTR. Our data also imply that modulators of p75NTR signaling could be developed as medications for alcohol abuse disorders.

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Striatal Adenosine Signaling Regulates EAAT2 and Astrocytic AQP4 Expression and Alcohol Drinking in Mice

Cited by 56 publications

References 46 publications

Adenosinergic Regulation of Striatal Clock Gene Expression and Ethanol Intake During Constant Light

Adenosinergic Regulation of Striatal Clock Gene Expression and Ethanol Intake During Constant Light

The Neuroimmune Transcriptome and Alcohol Dependence: Potential for Targeted Therapies

The Neurotrophic Factor Receptor p75 in the Rat Dorsolateral Striatum Drives Excessive Alcohol Drinking

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