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Glutamate and Brain Glutaminases in Drug Addiction

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Abstract

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.

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Fig. 1
Fig. 2

(adapted from reference [63])

Fig. 3

(adapted from references [63–66])

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Abbreviations

DA:

Dopamine

eCB:

Endocannabinoids

GA:

Glutaminase

GAB:

Gls2-encoded long glutaminase protein variant

GAC:

Gls-encoded short glutaminase protein variant

Gls :

Glutaminase gene encoding the kidney-type isoforms

Gls2 :

Glutaminase gene encoding the liver-type isoforms

KGA:

Gls-encoded long glutaminase protein variant

LGA:

Gls2-encoded short glutaminase protein variant

LPA:

Lysophosphatidic acid

MMP:

Matrix metalloproteinase

MSN:

Medium spiny neurons

NrCAM:

Neuron-glial related cell adhesion molecule

PLG:

Prolyl-leucyl-glycinamide

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Acknowledgements

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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Authors and Affiliations

  1. Canceromics Lab, Departamento de Biología Molecular y Bioquímica, Facultad de Ciencias, Universidad de Málaga, Campus de Teatinos, 29071, Málaga, Spain

    Javier Márquez, José A. Campos-Sandoval, Ana Peñalver, José M. Matés, Juan A. Segura & Francisco J. Alonso

  2. Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain

    Javier Márquez

  3. Unidad de Gestión Clínica de Salud Mental, IBIMA, Hospital Regional Universitario, 29010, Málaga, Spain

    Eduardo Blanco & Fernando Rodríguez de Fonseca

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  1. Javier Márquez
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  2. José A. Campos-Sandoval
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Correspondence to Javier Márquez.

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Special Issue: In Honor of Professor Jan Albrecht.

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Márquez, J., Campos-Sandoval, J.A., Peñalver, A. et al. Glutamate and Brain Glutaminases in Drug Addiction. Neurochem Res 42, 846–857 (2017). https://doi.org/10.1007/s11064-016-2137-0

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