Targeting glutamate uptake to treat alcohol use disorders

P. S S Rao, Richard Bell, Eric Engleman, Youssef Sari

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Alcoholism is a serious public health concern that is characterized by the development of tolerance to alcohol's effects, increased consumption, loss of control over drinking and the development of physical dependence. This cycle is often times punctuated by periods of abstinence, craving and relapse. The development of tolerance and the expression of withdrawal effects, which manifest as dependence, have been to a great extent attributed to neuroadaptations within the mesocorticolimbic and extended amygdala systems. Alcohol affects various neurotransmitter systems in the brain including the adrenergic, cholinergic, dopaminergic, GABAergic, glutamatergic, peptidergic, and serotonergic systems. Due to the myriad of neurotransmitter and neuromodulator systems affected by alcohol, the efficacies of current pharmacotherapies targeting alcohol dependence are limited. Importantly, research findings of changes in glutamatergic neurotransmission induced by alcohol self- or experimenter-administration have resulted in a focus on therapies targeting glutamatergic receptors and normalization of glutamatergic neurotransmission. Glutamatergic receptors implicated in the effects of ethanol include the ionotropic glutamate receptors (AMPA, Kainate, and NMDA) and some metabotropic glutamate receptors. Regarding glutamatergic homeostasis, ceftriaxone, MS-153, and GPI-1046, which upregulate glutamate transporter 1 (GLT1) expression in mesocorticolimbic brain regions, reduce alcohol intake in genetic animal models of alcoholism. Given the hyperglutamatergic/hyperexcitable state of the central nervous system induced by chronic alcohol abuse and withdrawal, the evidence thus far indicates that a restoration of glutamatergic concentrations and activity within the mesocorticolimbic system and extended amygdala as well as multiple memory systems holds great promise for the treatment of alcohol dependence.

Original languageEnglish
Article number144
JournalFrontiers in Neuroscience
Volume9
Issue numberAPR
DOIs
StatePublished - 2015

Fingerprint

Alcoholism
Glutamic Acid
Alcohols
Neurotransmitter Agents
Amygdala
Synaptic Transmission
Ionotropic Glutamate Receptors
Amino Acid Transport System X-AG
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Metabotropic Glutamate Receptors
Ceftriaxone
Kainic Acid
Genetic Models
Brain
N-Methylaspartate
Adrenergic Agents
Cholinergic Agents
Drinking
Homeostasis
Ethanol

Keywords

  • Alcohol
  • Dopamine
  • EAAT2
  • GLT1
  • Glutamate
  • Neurotransmitter

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Targeting glutamate uptake to treat alcohol use disorders. / Rao, P. S S; Bell, Richard; Engleman, Eric; Sari, Youssef.

In: Frontiers in Neuroscience, Vol. 9, No. APR, 144, 2015.

Research output: Contribution to journalArticle

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