Role of astrocytic glutamate transporter in alcohol use disorder - PubMed (original) (raw)

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Role of astrocytic glutamate transporter in alcohol use disorder

Jennifer R Ayers-Ringler et al. World J Psychiatry. 2016.

Abstract

Alcohol use disorder (AUD) is one of the most widespread neuropsychiatric conditions, having a significant health and socioeconomic impact. According to the 2014 World Health Organization global status report on alcohol and health, the harmful use of alcohol is responsible for 5.9% of all deaths worldwide. Additionally, 5.1% of the global burden of disease and injury is ascribed to alcohol (measured in disability adjusted life years, or disability adjusted life years). Although the neurobiological basis of AUD is highly complex, the corticostriatal circuit contributes significantly to the development of addictive behaviors. In-depth investigation into the changes of the neurotransmitters in this circuit, dopamine, gamma-aminobutyricacid, and glutamate, and their corresponding neuronal receptors in AUD and other addictions enable us to understand the molecular basis of AUD. However, these discoveries have also revealed a dearth of knowledge regarding contributions from non-neuronal sources. Astrocytes, though intimately involved in synaptic function, had until recently been noticeably overlooked in their potential role in AUD. One major function of the astrocyte is protecting neurons from excitotoxicity by removing glutamate from the synapse via excitatory amino acid transporter type 2. The importance of this key transporter in addiction, as well as ethanol withdrawal, has recently become evident, though its regulation is still under investigation. Historically, pharmacotherapy for AUD has been focused on altering the activity of neuronal glutamate receptors. However, recent clinical evidence has supported the animal-based findings, showing that regulating glutamate homeostasis contributes to successful management of recovery from AUD.

Keywords: Addiction; Alcohol; Astrocyte; Excitatory amino acid transporter type 2; Glia; Glutamate; Striatum.

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Figures

Figure 1

Figure 1

Fine regulation of glutamate levels and excitatory amino acid transporter 2 localization in neuron-glial interaction. The perisynaptic astrocytic process contains a higher concentration of EAAT2 immediately adjacent to the synapse. The EAP also contains EAAT2, but in lower concentrations. Glutamate spillover results in activation of GluN2B-containing NMDA receptors (increasing LTD response in the post-synaptic neuron), increased EAAT2 surface expression on and migration of EAPs, and activation of adjacent astrocytes via calcium waves propagated through connexin channels. LTP: Long term potentiation; LTD: Long term depression; EAAT2: Excitatory amino acid transporter 2; Xc-: Cysteine-glutamate transporter; ENT1: Equilibrative nucleoside transporter 1; VGLUT1: Vesicular glutamate transporter 1; NMDA: N-Nitrosodimethylamine; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; EAP: Extrasynaptic astrocytic process.

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