Neurochemical Research

, Volume 42, Issue 3, pp 846–857 | Cite as

Glutamate and Brain Glutaminases in Drug Addiction

  • Javier MárquezEmail author
  • José A. Campos-Sandoval
  • Ana Peñalver
  • José M. Matés
  • Juan A. Segura
  • Eduardo Blanco
  • Francisco J. Alonso
  • Fernando Rodríguez de Fonseca
Original Paper


Glutamate is the principal excitatory neurotransmitter in the central nervous system and its actions are related to the behavioral effects of psychostimulant drugs. In the last two decades, basic neuroscience research and preclinical studies with animal models are suggesting a critical role for glutamate transmission in drug reward, reinforcement, and relapse. Although most of the interest has been centered in post-synaptic glutamate receptors, the presynaptic synthesis of glutamate through brain glutaminases may also contribute to imbalances in glutamate homeostasis, a key feature of the glutamatergic hypothesis of addiction. Glutaminases are the main glutamate-producing enzymes in brain and dysregulation of their function have been associated with neurodegenerative diseases and neurological disorders; however, the possible implication of these enzymes in drug addiction remains largely unknown. This mini-review focuses on brain glutaminase isozymes and their alterations by in vivo exposure to drugs of abuse, which are discussed in the context of the glutamate homeostasis theory of addiction. Recent findings from mouse models have shown that drugs induce changes in the expression profiles of key glutamatergic transmission genes, although the molecular mechanisms that regulate drug-induced neuronal sensitization and behavioral plasticity are not clear.


Glutaminase Cocaine Drugs of abuse Glutamate Glutamatergic neuroadaptations Synaptic plasticity 









Gls2-encoded long glutaminase protein variant


Gls-encoded short glutaminase protein variant


Glutaminase gene encoding the kidney-type isoforms


Glutaminase gene encoding the liver-type isoforms


Gls-encoded long glutaminase protein variant


Gls2-encoded short glutaminase protein variant


Lysophosphatidic acid


Matrix metalloproteinase


Medium spiny neurons


Neuron-glial related cell adhesion molecule





This review is dedicated to Professor Dr. Jan Albrecht to celebrate his prolific and outstanding career in neurosciences. His inspiration about the differential roles of glutaminase isoforms in human glioblastoma has led to fruitful collaborations between our groups and, more important, to enjoy the privilege of a sincere friendship with him and many of his colleagues (Monika, Magda, etc.). This work was financially supported by Grants RD12/0028/0013 (JM) and RD12/0028/0001 (FRF) of the RTA RETICS network from the Spanish Health Institute Carlos III, Grant SAF2015-64501-R from the Spanish Ministry of Economy and Competitivity (to JM and JMM) and Excellence Grant CVI-6656 (Regional Andalusian government) (to JM).


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Javier Márquez
    • 1
    • 2
    Email author
  • José A. Campos-Sandoval
    • 1
  • Ana Peñalver
    • 1
  • José M. Matés
    • 1
  • Juan A. Segura
    • 1
  • Eduardo Blanco
    • 3
  • Francisco J. Alonso
    • 1
  • Fernando Rodríguez de Fonseca
    • 3
  1. 1.Canceromics Lab, Departamento de Biología Molecular y Bioquímica, Facultad de CienciasUniversidad de MálagaMálagaSpain
  2. 2.Instituto de Investigación Biomédica de Málaga (IBIMA)MálagaSpain
  3. 3.Unidad de Gestión Clínica de Salud Mental, IBIMAHospital Regional UniversitarioMálagaSpain

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