Role of group II metabotropic glutamate receptors in ketamine's antidepressant actions.

Major Depressive Disorder (MDD) is a serious neuropsychiatric disorder afflicting around 16-17 % of the global population and is accompanied by recurrent episodes of low mood, hopelessness and suicidal thoughts. Current pharmacological interventions take several weeks to even months for an improvement in depressive symptoms to emerge, with a significant percentage of individuals not responding to these medications at all, thus highlighting the need for rapid and effective next-generation treatments for MDD. Pre-clinical studies in animals have demonstrated that antagonists of the metabotropic glutamate receptor subtype 2/3 (mGlu2/3 receptor) exert rapid antidepressant-like effects, comparable to the actions of ketamine. Therefore, it is possible that mGlu2 or mGlu3 receptors to have a regulatory role on the unique antidepressant properties of ketamine, or that convergent intracellular mechanisms exist between mGlu2/3 receptor signaling and ketamine's effects. Here, we provide a comprehensive and critical evaluation of the literature on these convergent processes underlying the antidepressant action of mGlu2/3 receptor inhibitors and ketamine. Importantly, combining sub-threshold doses of mGlu2/3 receptor inhibitors with sub-antidepressant ketamine doses induce synergistic antidepressant-relevant behavioral effects. We review the evidence supporting these combinatorial effects since sub-effective dosages of mGlu2/3 receptor antagonists and ketamine could reduce the risk for the emergence of significant adverse events compared with taking normal dosages. Overall, deconvolution of ketamine's pharmacological targets will give critical insights to influence the development of next-generation antidepressant treatments with rapid actions.

mGlu2/3 receptor antagonists for depression: overview of underlying mechanisms and clinical development.

Triggered by the ground-breaking finding that ketamine exerts robust and rapid-acting antidepressant effects in patients with treatment-resistant depression, glutamatergic systems have attracted attention as targets for the development of novel antidepressants. Among glutamatergic systems, group II metabotropic glutamate (mGlu) receptors, consisting of mGlu2 and mGlu3 receptors, are of interest because of their modulatory roles in glutamatergic transmission. Accumulating evidence has indicated that mGlu2/3 receptor antagonists have antidepressant-like effects in rodent models that mirror those of ketamine and that mGlu2/3 receptor antagonists also share underlying mechanisms with ketamine that are responsible for these antidepressant-like actions. Importantly, contrary to their antidepressant-like profile, preclinical studies have revealed that mGlu2/3 receptor antagonists are devoid of ketamine-like adverse effects, such as psychotomimetic-like behavior, abuse potential and neurotoxicity. Despite some discouraging results for an mGlu2/3 receptor antagonist decoglurant (classified as a negative allosteric modulator [NAM]) in patients with major depressive disorder, clinical trials of two mGlu2/3 receptor antagonists, a phase 2 trial of TS-161 (an orthosteric antagonist) and a phase 1 trial of DSP-3456 (a NAM), are presently on-going. mGlu2/3 receptors still hold promise for the development of safer and more efficacious antidepressants.

Presynaptic 5-HT2A-mGlu2/3 Receptor-Receptor Crosstalk in the Prefrontal Cortex: Metamodulation of Glutamate Exocytosis.

The glutamatergic nerve endings of a rat prefrontal cortex (PFc) possess presynaptic 5-HT2A heteroreceptors and mGlu2/3 autoreceptors, whose activation inhibits glutamate exocytosis, and is measured as 15 mM KCl-evoked [3H]D-aspartate ([3H]D-asp) release (which mimics glutamate exocytosis). The concomitant activation of the two receptors nulls their inhibitory activities, whereas blockade of the 5-HT2A heteroreceptors with MDL11,939 (1 µM) strengthens the inhibitory effect elicited by the mGlu2/3 receptor agonist LY329268 (1 µM). 5-HT2A receptor antagonists (MDL11,939; ketanserin; trazodone) amplify the impact of low (3 nM) LY379268. Clozapine (0.1-10 µM) mimics the 5-HT2A agonist (±) DOI and inhibits the KCl-evoked [3H]D-asp overflow in a MDL11,939-dependent fashion, but does not modify the (±) DOI-induced effect. mGlu2 and 5-HT2A proteins do not co-immunoprecipitate from synaptosomal lysates, nor does the incubation of PFc synaptosomes with MDL11,939 (1 µM) or clozapine (10 µM) modify the insertion of mGlu2 subunits in synaptosomal plasma membranes. In conclusion, 5-HT2A and mGlu2/3 receptors colocalize, but do not physically associate, in PFc glutamatergic terminals, where they functionally interact in an antagonist-like fashion to control glutamate exocytosis. The mGlu2/3-5-HT2A metamodulation could be relevant to therapy for central neuropsychiatric disorders, including schizophrenia, but also unveil cellular events accounting for their development, which also influence the responsiveness to drugs regimens.

The role of mGlu2/3 receptor antagonists in the enhancement of the antidepressant-like effect of ketamine.

MGlu2/3 receptor antagonists produce antidepressant-like effects in animal models of depression. A number of mechanisms responsible for these actions are convergent to the mechanism of the fast antidepressant-like effect of ketamine. Furthermore, the data indicate that ketamine effect is related to the action of mGlu2 receptors and may be reduced by their agonists. The above facts became the basis for the hypothesis that the antidepressant effect of low doses of ketamine might be enhanced by coadministration of a mGlu2 receptor antagonist. This strategy was aimed not only at enhancing the therapeutic effect of ketamine but also at reducing the risk of undesirable effects by lowering its therapeutic dose. It is known that ketamine, effective in relieving depressive symptoms in patients suffering from treatment-resistant depression (TRD), is burdened with a number of side effects, which may be particularly dangerous in psychiatric patients. Data have confirmed that subeffective doses of ketamine and its enantiomer, (R)-ketamine, coadministered with an mGlu2/3 receptor antagonist, induce antidepressant-like effects in the screening tests and in the chronic-stress-induced model of depression. At the same time, these drug combinations did not cause undesirable effects characteristic of higher doses of ketamine and (S)-ketamine, including those related to psychostimulatory effects. Further research is required to prove whether this strategy will also be effective in depressive patients.

Antidepressant-like actions of the mGlu2/3 receptor antagonist TP0178894 in the chronic social defeat stress model: Comparison with escitalopram.

The metabotropic glutamate 2/3 (mGlu2/3) receptor antagonists are reported to produce ketamine-like rapid-acting and sustained antidepressant-like effects in rodents. In this study, we compared the effects of single administration of the new mGlu2/3 receptor antagonist TP0178894 and the selective serotonin reuptake inhibitor (SSRI) escitalopram in the chronic social defeat stress (CSDS) model of depression, a model which has been shown to be resistant to treatment with a single dose of SSRI. In the tail suspension test and forced swimming test, high dose (3.0 mg/kg) of TP0178894 significantly attenuated the increased immobility time of these tests in CSDS susceptible mice, compared with vehicle-treated mice. In contrast, low doses (0.3 and 1.0 mg/kg) of TP0178894 and escitalopram (10 mg/kg) did not alter the increased immobility time of these two tests. In the sucrose preference test, TP0178894 (3.0 mg/kg) significantly improved the reduced sucrose preference of CSDS susceptible mice, three and seven days after a single dose. In addition, Western blot analyses showed that TP0178894 (3.0 mg/kg), but not low doses of TP0178894 and escitalopram, significantly attenuated the reduced expression of synaptic proteins [α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (GluA1) and postsynaptic density protein 95 (PSD-95)] in the prefrontal cortex from CSDS susceptible mice. This study suggests that TP0178894 shows rapid-acting and sustained antidepressant-like effects in CSDS model, as ketamine does.

Evaluation of the Safety, Tolerability, and Pharmacokinetic Profiles of TP0473292 (TS-161), A Prodrug of a Novel Orthosteric mGlu2/3 Receptor Antagonist TP0178894, in Healthy Subjects and Its Antidepressant-Like Effects in Rodents.

BACKGROUND: TP0473292 (the active ingredient of TS-161) is a prodrug of a novel metabotropic glutamate (mGlu) 2/3 receptor antagonist being developed for the treatment of patients with depression. This study evaluated the safety, tolerability, and pharmacokinetics of orally administered TS-161 in healthy subjects. METHODS: This was a first-in-human, phase 1, randomized, double-blind, placebo-controlled, single-ascending dose (15-400 mg TS-161) and 10-day multiple-ascending dose (50-150 mg TS-161) study in healthy subjects, conducted from June 2019 through February 2020. Plasma and urine concentrations of the prodrug and its metabolites, and cerebrospinal fluid (CSF) concentrations of the active metabolite TP0178894 were measured to evaluate the pharmacokinetic profiles after oral administration of TS-161. RESULTS: Following single and multiple doses, TP0473292 was extensively converted into its active metabolite TP0178894. Plasma concentrations of TP0178894 reached peak (Cmax) within 5 hours post dose and declined with a t1/2 <13 hours. Plasma exposures of TP0178894 increased with increasing dose. TP0178894 penetrated into CSF and reached a Cmax of 9.892 ng/mL at a single dose of 100 mg, which was comparable with IC50 values of antagonist activity at mGlu2/3 receptors. The most frequently observed adverse events that showed exposure-related incidence during the study were nausea, vomiting, and dizziness. CONCLUSIONS: The mGlu2/3 receptor antagonist prodrug TP0473292 is safe and well-tolerated, is orally bioavailable in humans with extensive conversion into the active metabolite TP0178894 with sufficient CSF penetration to exert the anticipated pharmacological effects, and is a promising candidate for further clinical development in treatment of patients with depression.

The group II mGlu receptor antagonist LY341495 induces a rapid antidepressant-like effect and enhances the effect of ketamine in the chronic unpredictable mild stress model of depression in C57BL/6J mice.

Ketamine produces a rapid antidepressant effect, but its use can be associated with serious side effects. Hence, other therapeutic options that will allow us to obtain a quick and safe antidepressant effect by modulating glutamatergic transmission are needed. Antagonists of mGlu2/3 receptors, which share some mechanisms of action with ketamine, may be good candidates to obtain this effect. Here, we show that the metabotropic glutamate (mGlu) 2/3 receptor antagonist LY341495 induced a dose-dependent antidepressant-like effect in the chronic unpredictable mild stress (CUMS) model of depression in C57BL/6J mice after both single and subchronic (three-day) administration. Furthermore, a noneffective dose of LY341495 (0.3 mg/kg) given jointly with a noneffective dose of ketamine (3 mg/kg) reversed the CUMS-induced behavioral effects, indicating that coadministration of ketamine with an mGlu2/3 receptor antagonist might allow its therapeutically effective dose to be lowered. Western blot results indicate that mTOR pathway activation might be involved in the mechanism of action of this drug combination. Moreover, the combined doses of both substances did not produce undesirable behavioral effects characteristic of a higher dose of ketamine (10 mg/kg) commonly used in rodent studies to induce antidepressant effects. Coadministration of low doses of ketamine and LY341495 did not induce the hyperactivity typical of NMDA channel blockers, did not disturb short-term memory in the novel object recognition (NOR) test, and did not disturb motor coordination in the rotarod test. Our research not only confirmed the earlier data on the rapid antidepressant effect of mGlu2/3 receptor antagonists but also indicated that such compounds can safely lower the effective dose of ketamine.

Acute Low Dose of Trazodone Recovers Glutamate Release Efficiency and mGlu2/3 Autoreceptor Impairments in the Spinal Cord of Rats Suffering From Chronic Sciatic Ligation.

We investigated whether chronic sciatic ligation modifies the glutamate release in spinal cord nerve endings (synaptosomes) as well as the expression and the function of presynaptic release-regulating mGlu2/3 autoreceptors and 5-HT2A heteroreceptors in these particles. Synaptosomes were from the spinal cord of animals suffering from the sciatic ligation that developed on day 6 post-surgery a significant decrease of the force inducing paw-withdrawal in the lesioned paw. The exocytosis of glutamate (quantified as release of preloaded [3H]D-aspartate, [3H]D-Asp) elicited by a mild depolarizing stimulus (15 mM KCl) was significantly increased in synaptosomes from injured rats when compared to controls (uninjured rats). The mGlu2/3 agonist LY379268 (1000 pM) significantly inhibited the 15 mM KCl-evoked [3H]D-Asp overflow from control synaptosomes, but not in terminals isolated from injured animals. Differently, a low concentration (10 nM) of (±) DOI, unable to modify the 15 mM KCl-evoked [3H]D-Asp overflow in control spinal cord synaptosomes, significantly reduced the glutamate exocytosis in nerve endings isolated from the injured rats. Acute oral trazodone (TZD, 0.3 mg/kg on day 7 post-surgery) efficiently recovered glutamate exocytosis as well as the efficiency of LY379268 in inhibiting this event in spinal cord synaptosomes from injured animals. The sciatic ligation significantly reduced the expression of mGlu2/3, but not of 5-HT2A, receptor proteins in spinal cord synaptosomal lysates. Acute TZD recovered this parameter. Our results support the use of 5-HT2A antagonists for restoring altered spinal cord glutamate plasticity in rats suffering from sciatic ligation.

mGlu2/3 receptor as a novel target for rapid acting antidepressants.

Given that ketamine, a noncompetitive N-methyl-d-aspartate receptor antagonist that exerts rapid antidepressant effects in patients with treatment-resistant depression, also has undesirable adverse effects, agents that can be used as alternatives to ketamine have been actively pursued. Group II metabotropic glutamate (mGlu) receptors, consisting of mGlu2 and mGlu3 receptors, have emerged as one of the most promising targets in the development of ketamine-like antidepressants. Indeed, mGlu2/3 receptor antagonists have been demonstrated to exert rapid antidepressant effects in animal models and to be efficacious in animal models refractory to conventional antidepressants. Moreover, there are striking similarities between mGlu2/3 receptor antagonists and ketamine in terms of not only their antidepressant profiles, but also the underlying mechanisms of their antidepressant effects. Nonetheless, studies in rodents have shown that mGlu2/3 receptor antagonists do not cause ketamine-like adverse events, such as psychotomimetic-like behavior, abuse potential or neurotoxicity, supporting the usefulness of mGlu2/3 receptor antagonists as alternatives to ketamine. In this chapter, the past and recent research on the antidepressant effects of mGlu2/3 receptor antagonists will be reviewed. In particular, the potential of mGlu2/3 receptor antagonists as novel ketamine-like antidepressants will be emphasized.

Discovery of MGS0274, an ester prodrug of a metabotropic glutamate receptor 2/3 agonist with improved oral bioavailability.

We previously reported that MGS0008 is a selective group II metabotropic glutamate receptor (mGlu2/3 receptor) agonist that is effective in animal models of schizophrenia. MGS0008 is a highly hydrophilic glutamate analog and is therefore expected to show low oral bioavailability in humans. To improve the oral bioavailability of MGS0008, ester prodrugs of MGS0008 were synthesized and their usefulness was evaluated. Among the prodrugs, the l-menthol-ester prodrug 4h demonstrated preferable lipophilicity, good chemical stability, and a high conversion rate to MGS0008 in human and monkey liver microsomes. A pharmacokinetic study in monkeys revealed that the oral bioavailability of MGS0008 after oral dosing of compound 4h was approximately 15-fold higher than that after oral dosing of MGS0008. Based on these findings, a diastereomer of compound 4h (compound 4j, or MGS0274), was selected as a candidate for clinical drug development, and its besylate is currently under development for the treatment of schizophrenia (Development code: TS-134).

mGlu2/3 receptor antagonism: A mechanism to induce rapid antidepressant effects without ketamine-associated side-effects.

The consensus that ketamine can produce rapid-onset antidepressant effects in patients combined with the recent approval of S(+)-ketamine (esketamine, Spravato) as an antidepressant, has fueled the search for other compounds that might recapitulate the remarkable therapeutic benefits of ketamine. At the same time, discovery efforts have been additionally directed toward minimization of the tolerability, side-effect, and safety issues associated with ketamine. The history of thought on the viability of metabotropic 2/3 (mGlu2/3) receptor antagonism as a potential mechanism for inducing rapid-acting antidepressant effects is reviewed here. The biological basis for predicting antidepressant efficacy of mGlu2/3 receptor antagonists in depressed patients is also presented. This prediction is based upon convergent biochemical, neurochemical, electrophysiological, and behavioral data that indicate a striking homology in the substrates that underlie the effects of mGlu2/3 receptor antagonists and the known antidepressant ketamine. The data reviewed to date also demonstrate that the preclinical side-effect/tolerability and toxicology profile of mGlu2/3 receptor antagonists are not concerning. Finally, preclinical data on a relatively new mGlu2/3 receptor antagonist, LY3020371, and its orally-bioavailable prodrug, LY3027788, are reviewed. The data on this mechanism provides optimism for successful translation of the mGlu2/3 receptor antagonist hypothesis into therapeutics for those suffering from depression.

The mGluR2/3 agonist LY379268 reverses NMDA receptor antagonist effects on cortical gamma oscillations and phase coherence, but not working memory impairments, in mice.

BACKGROUND: Abnormalities in neural oscillations that occur in the gamma frequency range (30-80 Hz) may underlie cognitive deficits in schizophrenia. Both cognitive impairments and gamma oscillatory disturbances can be induced in healthy people and rodents by administration of N-methyl-D-aspartate receptor (NMDAr) antagonists. AIMS: We studied relationships between cognitive impairment and gamma abnormalities following NMDAr antagonism, and attempted to reverse deficits with the metabotropic glutamate receptor type 2/3 (mGluR2/3) agonist LY379268. METHODS: C57/Bl6 mice were trained to perform the Trial-Unique Nonmatching to Location (TUNL) touchscreen test for working memory. They were then implanted with local field potential (LFP) recording electrodes in prefrontal cortex and dorsal hippocampus. Mice were administered either LY379268 (3 mg/kg) or vehicle followed by the NMDAr antagonist MK-801 (0.3 or 1 mg/kg) or vehicle prior to testing on the TUNL task, or recording LFPs during the presentation of an auditory stimulus. RESULTS: MK-801 impaired working memory and increased perseveration, but these behaviours were not improved by LY379268 treatment. MK-81 increased the power of ongoing gamma and high gamma (130-180 Hz) oscillations in both brain regions and regional coherence between regions, and these signatures were augmented by LY379268. However, auditory-evoked gamma oscillation deficits caused by MK-801 were not affected by LY379268 pretreatment. CONCLUSIONS: NMDA receptor antagonism impairs working memory in mice, but this is not reversed by stimulation of mGluR2/3. Since elevations in ongoing gamma power and regional coherence caused by MK-801 were improved by LY379268, it appears unlikely that these specific oscillatory abnormalities underlie the working memory impairment caused by NMDAr antagonism.

Preclinical disposition of MGS0274 besylate, a prodrug of a potent group II metabotropic glutamate receptor agonist MGS0008 for the treatment of schizophrenia.

MGS0274 besylate is an ester-based lipophilic prodrug of a metabotropic glutamate (mGlu) 2 and mGlu3 receptor agonist MGS0008 and being developed for the treatment of schizophrenia. We investigated the disposition of these compounds in rats and monkeys and in vitro metabolism in humans to evaluate whether MGS0274 besylate could be useful as a prodrug in humans. After the oral administration of MGS0274 besylate to monkeys (2.89 mg/kg), MGS0008 was immediately found in plasma, reached a maximum concentration at 4 hours postdose, and decreased with a terminal half-life of 16.7 hours; MGS0274 was barely detectable. The oral bioavailability as MGS0008 was 83.7%, which was approximately 20-fold greater than that after oral dosing of MGS0008 (3.8%). In rats, MGS0008 penetrated the cerebrospinal fluid and was eliminated slower than from plasma. The in vitro metabolism study indicated that MGS0274 was rapidly hydrolyzed to MGS0008, which was not further metabolized. After the intravenous administration of MGS0008 to rats and monkeys, almost all the dose was excreted unchanged in urine. These results suggested that MGS0274 was, as expected, presystemically hydrolyzed to MGS0008 after gastrointestinal absorption and that MGS0008 was distributed throughout the body without further metabolism and ultimately excreted in urine in the animals. Furthermore, the hydrolytic activity against MGS0274 in the human liver S9 fraction was comparable to that in monkeys, suggesting the possibility of the rapid presystemic hydrolysis of MGS0274 to MGS0008 in humans, as it is in monkeys. Consequently, MGS0274 besylate is expected to function as a preferable prodrug in humans.

Rapid-acting antidepressants.

Conventional antidepressants (biogenic amine mechanisms) are not fully efficacious (e.g., symptoms remain after treatment, not all patients respond), produce effects only after weeks of daily dosing, and do not impact all disease symptoms. In contrast, a new class of antidepressants has been emerging since 2006 that has demonstrated rapid onset, large effect size, activity after only a single or few dose applications, and positive impact in treatment refractory patients and against some treatment-resistant symptoms (e.g., anhedonia). Rapid-acting antidepressant drug action has been demonstrated in controlled clinical studies for ketamine, a few other NMDA receptor antagonists, and scopolamine. Less clinical data are currently available for psychedelic drugs such as psilocybin, lysergic acid diethylamide, and ayahuasca. The mechanisms of action of rapid-acting antidepressants are not fully understood. However, a general triggering mechanism appears to involve the potentiation of AMPA receptor function. Although the durability of antidepressant effects of ketamine and scopolamine is limited, psychedelic drugs have been reported to produce effects for many months. The primary impediment to generating a medicine of this type for depressed patients is side effects and the lack of methods to ensure enduring antidepressant effects. Thus, further exploration of drug possibilities continues. Esketamine ((S)-ketamine) was recently FDA approved. Compounds currently in clinical development include the NMDA receptor antagonist (R)-ketamine, the NMDA receptor modulator, GLYX-13 (Rapastinel), and the AMPA receptor potentiator TAK-653. Additional pharmacological classes have produced effects in the preclinical laboratory to suggest their potential as rapid-acting agents. These include mGlu2/3 receptor antagonists, AMPA receptor potentiators, and negative allosteric modulators of GABAA(α5) receptors. In all cases, molecules exist that could be used to provide clinical proof of concept testing.

mGlu2/3 receptor antagonists.

Abnormalities of glutamatergic transmission are implicated in neuropsychiatric disorders. Among the glutamate receptors, metabotropic (mGlu) 2/3 receptors have recently gained much attention as molecular targets for the treatment of several neuropsychiatric disorders including depression and anxiety. Both orthosteric and allosteric antagonists of mGlu2/3 receptors have been synthesized, and their therapeutic potential has been examined. These research activities have demonstrated the promise of mGlu2/3 receptor antagonists as potential treatment agents for the above-mentioned neuropsychiatric disorders. In particular, it has been considered that the antidepressant effects of mGlu2/3 receptor antagonists are worthy of pursuing, since the antidepressant profiles as well as synaptic/neural mechanisms involved in the actions of mGlu2/3 receptor antagonists are similar to those of ketamine, which has been demonstrated to show potent, rapid and sustained efficacy in patients with depression, even those resistant to the conventionally prescribed antidepressants. In this chapter, the general pharmacology of mGlu2/3 receptor antagonists and their therapeutic potential are reviewed. In particular, I focus on the usefulness of mGlu2/3 receptor antagonists as novel antidepressants, in comparison with ketamine.

Role of Serotonergic System in the Antidepressant Actions of mGlu2/3 Receptor Antagonists: Similarity to Ketamine.

Numerous studies have demonstrated the antidepressant effects of group II metabotropic glutamate (mGlu2/3) receptor antagonists in various rodent models. Importantly, it has been shown that the antidepressant effects of mGlu2/3 receptor antagonists in rodent models are similar to those of ketamine, which exerts rapid and long-lasting antidepressant effects in patients with major depressive disorders, including patients with treatment-resistant depression. In addition, the synaptic mechanisms underlying the effects of mGlu2/3 receptor antagonists are reported to be similar to those underlying the effects of ketamine. The roles of the serotonergic system in the antidepressant effects of mGlu2/3 receptor antagonists have recently been demonstrated. Moreover, it was investigated how mGlu2/3 receptor antagonists interact with the serotonergic system to exert antidepressant effects. Notably, the same neural mechanisms as those underlying the effects of ketamine may be involved in the antidepressant actions of the mGlu2/3 receptor antagonists. In this review, we shall summarize the antidepressant potential of mGlu2/3 receptor antagonists and their mechanisms of action in comparison with those of ketamine. In particular, we shall focus on the roles of the serotonergic system in the antidepressant actions of mGlu2/3 receptor antagonists.

Rapid-Acting Antidepressants.

BACKGROUND: Conventional antidepressants are thought to produce their impact on clinical symptoms by increasing the central availability of biogenic amine neurotransmitters (the monoamine hypothesis of depression). These drugs continue to be the primary medicines used in major depressive disorder. Although they have biological effects after acute dosing, full antidepressant response generally takes weeks of daily administration. Lack of rapid onset is a large limitation in antidepressant therapy (e.g., suicide, lack of medication compliance, difficulty switching medications). METHODS: The present review of the literature discusses the preclinical and clinical findings on compounds that can produce immediate symptom relief. RESULTS: These compounds include ketamine, scopolamine, and mechanistically-related drugs. Newer additions to the list of potential rapid-acting agents include antagonists of metabotropic (mGlu) 2/3 receptors, negative allosteric modulators of α5-containing GABAA receptors, and psychedelic compounds. An additional benefit of these compounds is that they have demonstrated large effect sizes and, importantly, demonstrated efficacy in patient's refractory to other treatments. A drawback of some of these compounds, to date, is finding ways to expand the duration of clinical efficacy. In addition, for some compounds, the side-effect profile requires management. A primary mechanism by which rapid effects might be produced is through the amplification of excitatory neurotransmission through activation of AMPA receptors. The extracellular efflux of glutamate induced by these drugs has been documented and provides the hypothesized triggering mechanism for AMPA receptor amplification. CONCLUSION: The preclinical and clinical literature strongly suggests that rapid-acting antidepressants are the current focus of antidepressant drug discovery. Promising clinical findings exist for several compounds including ketamine and other NMDA receptor antagonists, scopolamine, and psilocybin. Two compounds are in late stage clinical development: GLYX-13 (Rapastinel) and eskekamine.

5-HT2A-mGlu2/3 receptor complex in rat spinal cord glutamatergic nerve endings: A 5-HT2A to mGlu2/3 signalling to amplify presynaptic mechanism of auto-control of glutamate exocytosis.

Presynaptic mGlu2/3 autoreceptors exist in rat spinal cord nerve terminals as suggested by the finding that LY379268 inhibited the 15 mM KCl-evoked release of [3H]D-aspartate ([3H]D-Asp) in a LY341495-sensitive manner. Spinal cord glutamatergic nerve terminals also possess presynaptic release-regulating 5-HT2A heteroreceptors. Actually, the 15 mM KCl-evoked [3H]D-Asp exocytosis from spinal cord synaptosomes was reduced by the 5-HT2A agonist (±)DOI, an effect reversed by the 5-HT2A antagonists MDL11,939, MDL100907, ketanserin and trazodone (TZD). We investigated whether mGlu2/3 and 5-HT2A receptors colocalize and cross-talk in these terminals and if 5-HT2A ligands modulate the mGlu2/3-mediated control of glutamate exocytosis. Western blot analysis and confocal microscopy highlighted the presence of mGlu2/3 and 5-HT2A receptor proteins in spinal cord VGLUT1 positive synaptosomes, where mGlu2/3 and 5-HT2A receptor immunoreactivities largely colocalize. Furthermore, mGlu2/3 immunoprecipitates from spinal cord synaptosomes were also 5-HT2A immunopositive. Interestingly, the 100 pM LY379268-induced reduction of the 15 mM KCl-evoked [3H]D-Asp overflow as well as its inhibition by 100 nM (±)DOI became undetectable when the two agonists were concomitantly added. Conversely, 5-HT2A antagonists (MDL11,939, MDL100907, ketanserin and TZD) reinforced the release-regulating activity of mGlu2/3 autoreceptors. Increased expression of mGlu2/3 receptor proteins in synaptosomal plasmamembranes paralleled the gain of function of the mGlu2/3 autoreceptors elicited by 5-HT2A antagonists. Based on these results, we propose that in spinal cord glutamatergic terminals i) mGlu2/3 and 5-HT2A receptors colocalize and interact one each other in an antagonist-like manner, ii) 5-HT2A antagonists are indirect positive allosteric modulator of mGlu2/3 autoreceptors controlling glutamate exocytosis.

Neuroadaptive changes in metabotropic glutamate mGlu2/3R expression during different phases of cocaine addiction in rats.

BACKGROUND: In the cocaine addiction the development from transient into persistent neuroplastic changes strongly involves the glutamatergic system. In this respect, among glutamatergic receptors special attention is paid to the group II of metabotropic glutamatergic receptors (mGlu2/3R) which are involved in the transition from drug use to drug addiction including the relapse mechanisms. METHODS: The present study employed radioligand binding and Western blot assays to study mGlu2/3R density, affinity and protein expression in selected rat brain areas after cocaine self-administration, extinction training and cocaine-induced reinstatement. Rats were randomly assigned in triads to one of three conditions: contingent cocaine intravenous self-administration, non-contingent injections of cocaine (yoked cocaine), or saline yoked to the intake of the self-administering subject. RESULTS: Cocaine self-administration and yoked cocaine delivery resulted in a significant increase in the mGlu2/3R density in the prefrontal cortex and the dorsal striatum, while 10-day extinction training provoked a reduction in the prefrontal cortex and the nucleus accumbens. Cocaine abstinence also enhanced an increase in the [3H]ligand binding to mGlu2/3R in the prefrontal cortex. During reinstatement the cocaine challenge dose (10mg/kg, ip) led to important elevation in the mGlu2/3R density in the prefrontal cortex. CONCLUSIONS: Our study demonstrated the role of mGlu2/3R localized in the prefrontal cortex-striatum pathways to cocaine repeated exposure.

mGlu2/3 Receptor Antagonists as Novel Antidepressants.

Based on the discovery of the robust antidepressant effects of ketamine in patients with depression, including those with treatment-resistant depression, agents acting on the glutamatergic system have drawn much attention as potential novel antidepressants. Among the agents acting on the glutamatergic system, preclinical data have indicated that the group II metabotropic glutamate (mGlu) receptors, mGlu2 and mGlu3, are attractive targets for the development of novel antidepressants. The antidepressant effects of mGlu2/3 receptor antagonists have been demonstrated in rodent models, and the synaptic and neural mechanisms underlying the antidepressant effects of these compounds have been investigated. Furthermore, these findings have indicated the similarities of the antidepressant effects and of the mechanisms underlying these effects between mGlu2/3 receptor antagonists and ketamine. Based on the results obtained hitherto, here I discuss the potential for mGlu2/3 receptor antagonists to be developed as next-generation antidepressants.