Glutamate plays a central role in the development and maintenance of addictive behaviors in all addictions as it alters reward signaling. Normalization of glutamate signaling should make a significant improvement in addictive behavior and underlying addiction.

This is not a comprehensive list, simply some articles I have found along the way.

“Traditionally, addiction research in neuroscience has focused on mechanisms involving dopamine and endogenous opioids. More recently, it has been realized that glutamate also plays a central role in processes underlying the development and maintenance of addiction. These processes include reinforcement, sensitization, habit learning and reinforcement learning, context conditioning, craving and relapse. In the past few years, some major advances have been made in the understanding of how glutamate acts and interacts with other transmitters (in particular, dopamine) in the context of processes underlying addiction. It appears that while many actions of glutamate derive their importance from a stimulatory interaction with the dopaminergic system, there are some glutamatergic mechanisms that contribute to addiction independent of dopaminergic systems. Among those, context-specific aspects of behavioral determinants (ie control over behavior by conditioned stimuli) appear to depend heavily on glutamatergic transmission. A better understanding of the underlying mechanisms might open new avenues to the treatment of addiction, in particular regarding relapse prevention.”

“A number of studies strongly suggest that glutamate receptors are also playing a major role in addictive behaviors.[,,] A combination of alcohol-related glutamate release and glutamate enhancement of addictive behaviors would make abstinence much more difficult.”

The ups and downs of addiction: role of metabotropic glutamate receptors “Drug addiction is characterized by drug-induced positive affect, followed by withdrawal-associated negative affect. Such drug-induced positive and negative affective states provide crucial sources of motivation that drive compulsive drug consumption. Metabotropic glutamate (mGlu) receptors, which are responsible for slow glutamate-mediated neurotransmission, are located throughout limbic and cortical brain regions that are implicated in drug addiction. Emerging evidence indicates that mGlu receptors regulate many behavioral actions of addictive drugs. In particular, group I mGlu receptors play an important role in regulating the reinforcing effects of drugs of abuse. Furthermore, group II mGlu receptors have been implicated in the synaptic adaptations that occur in response to chronic drug exposure and contribute to the aversive behavioral syndrome observed during withdrawal. These findings increase our understanding of the pathological processes that are associated with the development of drug addiction, and might ultimately lead to new therapies for the treatment of this disorder.”

Glutamate, a new player in addiction “Scientists have just identified in the mouse, and then confirmed in humans, a new factor that regulates addiction. Glutamate, a neurotransmitter1, contributes to regulating dopamine release in the nucleus accumbens, one of the cerebral structures of the reward system. More precisely, it is its subtle balance with another neurotransmitter – acetylcholine – that prevents up-regulation of the system and entry into addiction. This discovery, which opens up new therapeutic perspectives”

“Over the last two decades, there has been an increasing focus on the role of the excitatory neurotransmitter glutamate in drug addiction. In this review, pharmacological and genetic evidence supporting the role of glutamate in mediating the rewarding effects of the above described drugs of abuse will be discussed. Further, the review will discuss the role of glutamate transmission in two complex heterogeneous brain regions, namely the nucleus accumbens (NAcc) and the ventral tegmental area (VTA), which mediate the rewarding effects of drugs of abuse. In addition, several medications approved by the Food and Drug Administration that act by blocking glutamate transmission will be discussed in the context of drug reward. Finally, this review will discuss future studies needed to address currently unanswered gaps in knowledge, which will further elucidate the role of glutamate in the rewarding effects of drugs of abuse.”

“Here we propose three new perspectives on how the field might approach integrating and using the emerging data on glutamatergic adaptations. 1) Consider adaptations produced in kind across drug classes as most useful towards understanding shared characteristics of addiction, such as relapse. 2) Consider how drug-induced changes in glia and the extracellular matrix may contribute to synaptic alterations. 3) Make measurements not only at late withdrawal, but also during drug-seeking events to capture transient changes that mediate active drug seeking that are shared across drug classes.”

“Cortico-striatal glutamate transmission has been implicated in both the initiation and expression of addiction related behaviors, such as locomotor sensitization and drug-seeking. While glutamate transmission onto dopamine cells in the ventral tegmental area undergoes transient plasticity important for establishing addiction-related behaviors, glutamatergic plasticity in the nucleus accumbens is critical for the expression of these behaviors. This information points to the value of exploring pharmacotherapeutic manipulation of glutamate plasticity in treating drug addiction.”

Both glutamate and GABA play important roles in the reinforcing effects of nicotine and development of nicotine dependence. Chronic nicotine exposure facilitates excitatory glutamate neurotransmission, and repeated nicotine exposure attenuates inhibitory GABA neurotransmission. Overall, the preclinical data presented in this article strongly suggest that the substrates, such as receptors, transporters, or enzymes that regulate the actions of glutamate and GABA, may be useful targets for the treatment of nicotine dependence. Currently, medications that target either glutamate or GABA neurotransmission are being evaluated in human smokers. The next generation of glutamate- or GABA-based smoking cessation medications may have better efficacy and fewer adverse effects than the currently approved smoking cessation medications.”

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