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GABAAR α2-activated neuroimmune signal controls binge drinking and impulsivity through regulation of the CCL2/CX3CL1 balance

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Abstract

Background and Purpose

Toll-like receptors (TLRs) are a family of innate immune system receptors that respond to pathogen-derived and tissue damage-related ligands and are increasingly recognized for their impact on homeostasis and its dysregulation in the nervous system. TLR signaling participates in brain injury and addiction, but its role in the alcohol-seeking behavior, which initiates alcohol drinking, is still poorly understood. In this review, we discuss our findings designed to elucidate the potential contribution of the activated TLR4 signal located in neurons, on impulsivity and the predisposition to initiate alcohol drinking (binge drinking).

Results

Our findings indicate that the TLR4 signal is innately activated in neurons from alcohol-preferring subjects, identifying a genetic contribution to the regulation of impulsivity and the alcohol-seeking propensity. Signal activation is through the non-canonical, previously unknown, binding of TLR4 to the α2 subunit of the γ-aminobutyric 2 acid A receptor (GABAAR α2). Activation is sustained by the stress hormone corticotrophin-releasing factor (CRF) and additional still poorly recognized ligand/scaffold proteins. Focus is on the effect of TLR4 signal activation on the balance between pro- and anti-inflammatory chemokines [chemokine (C-C motif) ligand 2 (CCL2)/chemokine (C-X3-C motif) ligand 1 (CX3CL1)] and its effect on binge drinking.

Conclusion

The results are discussed within the context of current findings on the distinct activation and functions of TLR signals located in neurons, as opposed to immune cells. They indicate that the balance between pro- and anti-inflammatory TLR4 signaling plays a major role in binge drinking. These findings have major impact on future basic and translational research, including the development of potential therapeutic and preventative strategies.

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Authors and Affiliations

  1. Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Laure Aurelian & Irina Balan

  2. Stanford University School of Medicine OFDD, Stanford, CA, 94305, USA

    Laure Aurelian

  3. Department of Psychiatry and Pharmacology, Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Irina Balan

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  1. Laure Aurelian
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  2. Irina Balan
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Correspondence to Laure Aurelian.

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This article belongs to a Special Issue on Neuroimmune Signaling in Psychiatric Disease.

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Aurelian, L., Balan, I. GABAAR α2-activated neuroimmune signal controls binge drinking and impulsivity through regulation of the CCL2/CX3CL1 balance. Psychopharmacology 236, 3023–3043 (2019). https://doi.org/10.1007/s00213-019-05220-4

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