The glutamatergic synapse. Glutamate is packaged into synaptic vesicles in the presynaptic terminal by vGluT. When an action potential arrives at the terminal, glutamate is released by exocytosis into the synaptic cleft where it binds to and activates iGluRs (NMDA, AMPA and KA receptors) localized on the postsynaptic neuron, which results in cation influx and subsequent activation of VGCCs that propagate the action potential. The resulting cation influx can activate numerous second messenger systems, including PKA and CaMKII, which in turn interact with other signaling molecules or transcription factors can which modulate gene expression, local mRNA translation, or cytoskeletal remodeling. iGluR subunits can be phosphorylated by numerous kinases such as PKC, CaMKII, Fyn and others, altering the activity and functionality of these receptors. NMDA receptor subunits have recently been discovered to be expressed by glial cells and on presynaptic terminals (not shown). Glutamate can also be released into the extracellular space via nonexocytotic mechanisms such as cystine-glutamate-exchanger (x_c) located on glial cells. Whether released from the presynaptic terminal or neighboring glial cells, extracellular glutamate binds and activates not only iGluRs but also postsynaptic mGluRs in the perisynaptic annulus, which are either positively coupled to PKC activity and mobilize intracellular Ca²⁺ from IP₃-gated intracellular stores (as is the case for mGluR1 and 5) or negatively regulate AC (as is the case for mGluRs 2, 3, 4, 6, 7, and 8). Group I mGluRs positively regulate NMDA receptor function via PKC. Like iGluRs, mGluRs function can be altered by phosphorylation by various kinases. Glutamate release by the presynaptic terminal is negatively regulated by Group II or III mGluR autoreceptors, and is cleared from the extracellular space by EAATs located either on the presynaptic terminal, neighboring glial cells, or the postsynaptic neuron. In glia, glutamate is converted to glutamine, which is then transported back to the presynaptic terminal and converted back to glutamate. Although the numerous proteins that make up the postsynaptic density complex are not shown in this diagram, it should be noted that the Homer family of scaffolding of proteins links NMDA receptors to Group I mGluRs and IP₃-gated intracellular Ca²⁺ stores, and several recent studies implicate Homer proteins in psychostimulant and alcohol addiction (see Sections 4 and 9).

Hypothesized mechanism by which N-acetylcysteine (NAC) restores extracellular glutamate levels in the NAcc and prevents cocaine-induced reinstatement. (A) Cocaine self-administration induces glutamate release from prefrontal cortical neurons that synapse onto medium spiny neurons in the NAcc. (B) Repeated exposure to cocaine results in a desensitization of presynaptic Group II mGluRs and also down-regulates the efficacy of the cystine-glutamate exchanger (x_c), resulting in decreased extracellular glutamate levels during cocaine withdrawal. (C) NAC, a cystine pro-drug, is converted to cystine and drives x_c to transport glutamate from within glial cells into the extracellular environment. The resulting “normalization” of extracellular glutamate levels in the NAcc is believed to prevent further glutamate release produced by a priming injection of cocaine, thereby reducing subsequent reinstatement of cocaine-seeking behavior. See section 11.2 for more detail.

Graph showing the increasing number of publications on the topic of glutamate and addiction over the past 20 years. Two separate PubMed searches were performed in April 2007, one using “drug addiction” and “glutamate” as key words (open circles) and the other using “alcoholism” and “glutamate” as key words (filled circles). The resulting number of publications (including review articles and commentaries) are plotted by year for 1987 to 2006.

Sagittal section of the rodent brain showing neuroanatomical interactions between glutamate and mesolimbic dopamine systems. The “reward circuit” is hypothesized to consist of dopamine-synthesizing cell bodies in the VTA that project rostrally to innervate the NAcc, Amyg and FC, as well as other regions such as the portions of the CPu and ventral pallidum (not shown). This mesolimbic reward pathway is robustly innervated by glutamate-containing neurons. Dopamine-containing cell bodies in the VTA receive glutamatergic input from the PPT, LDT, Amyg and FC. The NAcc receives a host of glutamatergic innervation from the FC, Hipp, Thal, and Amyg. The FC receives glutamatergic input from the Hipp, Thal and Amyg. Drawing adapted from the atlas of Franklin and Paxinos [906]. Abbreviations: Amyg, amygdala; CPu, caudate-putamen (dorsal striatum); FC, frontal cortex; Hipp, hippocampus; LDT, laterodorsal tegmentum; NAcc, nucleus accumbens; PPT, pedunculopontine tegmentum; Thal, thalamus; VTA, ventral tegmental area.

Chemical structures of medications that act on glutamatergic transmission that have shown positive effects in the treatment of drug addiction and/or alcoholism in humans.