Glutamate hypothesis of schizophrenia - Wikipedia

In this commentary, we review the evidence for and against glutamate as a cotransmitter and discuss the potential role of glutamate‐DA corelease in addiction.

Medications That Normalize Brain Glutamate Reduce Drug-Seeking in ..

Glutamate regulates central nervous system function through the actions of ionotropic and metabotropic receptors. The involvement of glutamate in various psychiatric and medical conditions has been intensively examined. However, earlier work mostly focused on ionotropic glutamate receptors. In contrast to the fast and direct actions of ionotropic receptors, the three groups of metabotropic (mGlu) receptors modify neuronal activity through G-protein coupled signaling. Groups of mGluRs are distinguished by their pharmacological and intracellular signaling properties. mGluR5, which was first cloned in animals in 1992 and a few years later in humans, belongs to group I metabotropic receptors (Olive, ). Its actions are predominantly excitatory (Meldrum, ). Cleva and Olive () described strong links and receptor interactions between mGluR5 and NMDA receptor, suggesting that mGluR5 might also be extensively implicated in mediating neural plasticity as well as learning and memory processes. In addition, there is some evidence that mGluR5 activation enhances GABA, especially in the nucleus accumbens (Hoffpauir and Gleason, ). Thus, it is suggested that metabotropic glutamate receptor activity can modulate excitatory and inhibitory (GABA) signaling pathways. High mGluR5 receptor density was identified primarily in the forebrain regions, striatum, and limbic regions including the amygdala and hippocampus (Swanson et al., ). Using advanced molecular biological techniques to determine mGluR5 mRNA expression in the rodent brain, research determined that regions of the olfactory bulb, dorsal striatum, nucleus accumbens, lateral septum, and hippocampus show the highest levels of mGluR5 expression (Abe et al., ) (See Figure ).

glutamate homeostasis hypothesis of addiction

Many AEDs interact with both the GABA and glutamate neurotransmitter systems, and thus have the potential not only for benefit during withdrawal, but also to prevent relapse to substance use.


Non-competitive antagonists such as PCP and PCP-like compounds bind to a site within the NMDA ion channel at the PCP receptor site (there is also a Mg site within the ion channel). Binding inside the channel is dependent on the state of the ion channel (open or closed). Non-competitive antagonists such as PCP and PCP-like compounds appear to bind only when the channel is open. In the presence of NMDA agonists, binding of PCP to the receptor site is enhanced. Data from MacDonald et al. () provide some clues as to why PCP may have more potent effects than other PCP-like compounds (e.g., ketamine). Basically, the hypothesis is that once a compound binds to the PCP site, the ion channel closes and the trapped molecules cannot escape until the channel reopens. The potency of the drug is determined by its relative rate of escape from the open ion channel. The rate of escape for PCP molecules is 10 times slower than for ketamine—which may account for the higher potency of PCP, since it remains in the channel for longer periods of time (). However, since PCP and PCP-like compounds do not bind exclusively to the PCP receptor, sites such as other inotropic receptors, the metabotropic site, and the sigma site may also be involved in the production of psychotomimetic effects.

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Findings from a large number of preclinical animal trials have determined the effect of mGluR5 antagonist treatment in anxiety. Swanson et al. () reviewed animal studies on drugs targeting the mGluR5 on anxiety-like behaviors. They concluded that mGluR5 antagonistic treatment mostly led to anxiolytic responses in experimental animals. In particular, effects such as reduced fear conditioned freezing, increased shock and punishment acceptance, and increased social interactions were observed. For example, a single dose of 2-methyl-6-(phenylethynyl)pyridine (MPEP) increased the amount of time that rats spent in the open arm of an experimental maze, without affecting planning or motor behavior (Tatarczyńska et al., ). Krystal et al. () reviewed preclinical animal studies that examined mGluR5 antagonists (MTEP, MPEP, fenobam) in mouse models of anxiety. These studies used different outcome measures, such as extinction of fear conditioning and responses in the elevated plus maze, to assess the effectiveness of drug treatments. Of the studies examined, 88.45% reported an anxiolytic effect with mGluR5 antagonists (Krystal et al., ). More recently, another review on anxiety research in animal models that examined the effect of ionotropic and metabotropic glutamate receptor antagonist intervention was published (Riaza Bermudo-Soriano et al., ). Regarding mGluR5, the authors listed 43 animal studies of anxiety, and all but two demonstrated anxiolytic effects.