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.