Abstract

Evidence has demonstrated that deficits in glutamate transmission impair neurocircuits involved in drug abuse or drug-seeking behaviour and affect many aspects of neuroplasticity associated with alcohol and drug addiction. Alcohol-seeking behaviour is promoted by increased glutamate transmission in key regions of the mesocorticolimbic reward circuit, including the nucleus accumbens and prefrontal cortex. Glutamate transmission or glutamate uptake is regulated by a number of glutamate transporters in the brain regions. Among these glutamate transporters, glutamate transporter 1 (GLT1; its human homolog is the excitatory amino acid transporter 2, EAAT2) regulates the removal of majority of the extracellular glutamate. The role of GLT1 has been tested in alcohol and other drugs of abuse models with dysfunction in glutamate transmission. We recently reported that treatment of alcohol-preferring rats with compounds ceftriaxone and GPI-1046, known to upregulate GLT1 levels, showed reduction in alcohol intake and attenuation of relapse-like ethanol-drinking behaviour. Furthermore, we demonstrated that upregulation of GLT1 was associated with attenuation of cue-induced cocaine relapse. Together, we suggest that GLT1 is considered as a potential therapeutic target for the treatment of drug dependence, including alcohol. The aim of this critical review was to discuss the potential therapeutic role of GLT1 for the treatment of alcohol dependence. Dysfunction of glutamate transmission has been suggested to impair neurocircuits involved in alcohol dependence, which affect neuroplasticity that is associated with ethanol intake.

Highlights

  • IntroductionAlcohol abuse and dependence continue to be significant public health problems. A better understanding of their neurobiology will facilitate the development of interventions targeting prevention and/or treatment of these major health issues

  • Evidence has demonstrated that deficits in glutamate transmission impair neurocircuits involved in drug abuse or drug-seeking behaviour and affect many aspects of neuroplasticity associated with alcohol and drug addiction

  • The neurocircuitry of the glutamatergic system in the modulation of alcohol dependence and drugs of abuse is not fully defined, it is suggested that this system within the PFC19 and the NAc20 plays a critical role in drug reinforcement

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Summary

Introduction

Alcohol abuse and dependence continue to be significant public health problems. A better understanding of their neurobiology will facilitate the development of interventions targeting prevention and/or treatment of these major health issues. Focussing on the role of GLT1 in alcohol-drinking behaviour, we have previously reported that male alcohol-preferring (P) rats treated with ceftriaxone for five days, at different doses, showed a significant dose-dependent reduction in ethanol intake compared to saline-treated rats[15]. This reduction in ethanol intake was associated, in part, with the upregulation of GLT1 levels in the NAc and prefrontal cortex (PFC). We have recently reported that chronic alcohol consumption can lead to downregulation of GLT1 levels in the NAc18 These findings suggest that GLT1 upregulation or activation has potential for the treatment of alcohol dependence and other drugs of abuse. We have further discussed the importance of upregulation of GLT1 in chronic ethanol consumption and relapse-like ethanol drinking behaviour

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