Glutamate and Brain Glutaminases in Drug Addiction

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.

Large scale analysis of the diversity and complexity of the adult spinal cord neurotransmitter typology

“…Finally, neurotransmitter typology maps like that presented here are essential resources for clinical studies. Neurotransmitters are implicated in many neurological disorders, including schizophrenia, drug addiction, Parkinson's disease, autism, Alzheimer's disease, and attention deficit hyperactivity disorder (ADHD) (Abi-Dargham et al, 1997;Das et al, 2014;Huot et al, 2011;Márquez et al, 2017;Nakamura, 2013;Purkayastha et al, 2015;Rodríguez et al, 2012;Webster, 2001). Since neurotransmitter changes contribute to such diverse neurological disorders, comprehensive data on the diverse sets of neurons expressing specific neurotransmitters could enable the development of non-invasive therapies to restore nervous system function.…”

Expression of NMDA receptor subunits in human blood lymphocytes: A peripheral biomarker in online computer game addiction

“…However, evidence confirming the above statement is limited. It is now believed that glutamatergic transmission has a key role in the process of addiction development and it is considered as a possible novel target for pharmacological treatment of drug and behavioral addictions ( Márquez et al., 2017 ). The NMDA receptor as a tetramer-structured ionotropic glutamate receptor is significantly involved in many neuronal and organizational brain functions, such as fast excitatory transmission, synaptic plasticity, learning, and memory ( Glasgow et al., 2015 ).…”

Soluble iron accumulation induces microglial glutamate release in the spinal cord of sporadic amyotrophic lateral sclerosis

“…In relation to this, emerging evidence suggests that TNFα levels are increased in blood, CSF, and CNS of SALS patients, and that there is a link between TNFα‐related neuroinflammation and glutamate‐mediated excitotoxicity . GLS‐C is a TNFα‐upregulated inducible cytosolic enzyme which deaminizes glutamine to form glutamate, which is in turn released to the extracellular space . We were also interested in Ft, FPN, and hepcidin, based on evidence that Ft is upregulated by intracellular iron accumulation, and that hepcidin is upregulated by TNFα stimulation and binds to FPN, promoting internalization and degradation of FPN.…”

“…35 GLS-C is a TNFα-upregulated inducible cytosolic enzyme which deaminizes glutamine to form glutamate, which is in turn released to the extracellular space. [36][37][38] We were also interested in Ft, 6,7 FPN, 3,4,8 and hepcidin, 3,4 based on evidence that Ft is upregulated by intracellular iron accumulation, and that hepcidin is upregulated by TNFα stimulation and binds to FPN, promoting internalization and degradation of FPN. Thus, it is noteworthy to determine the relationship between iron and glutamate in SALS.…”