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The chronic unpredictable mild stress (CUMS) model of depression in mice is a model commonly used to investigate stress-induced depressive-like behaviours. The duration of the stress-inducing procedure is variable, thus making it difficult to compare results and draw general conclusions from different protocols. Here, we decided to investigate how the duration of the CUMS procedure affects behavioural changes, body weight as well as the level of plasma corticosterone in stressed and nonstressed C57BL/6J mice subjected to CUMS for 18 or 36 days. We found that 18 days of CUMS induced a robust decrease in grooming time in the splash test and a significant increase in the immobility time in the tail suspension test (TST) and the forced swim test (FST). All of these stress-induced depression-related behavioural effects diminished or even disappeared after 36 days of CUMS. Plasma corticosterone levels were increased in the CUMS mice compared to those in the nonstressed mice. However, this effect was more pronounced in mice stressed for 18 days. On the other hand, a gradual decline in weight loss in the stressed animals was observed as the duration of the CUMS procedure increased. Altogether, the results indicate that 18 days of CUMS did not affect body weight but caused significant behavioural effects as well as a robust increase in corticosterone levels, while 36 days of CUMS induced significant reduction in weight gain but only slight or even non-significant behavioural effects. These results may indicate the presence of adaptive changes to the long-term CUMS procedure in C57BL/6J mice.

Ketamine is an effective, rapid-acting antidepressant drug (RAAD), but it induces side effects. To overcome these challenges, attempts have been made to use safer enantiomer ((

(S)-ketamine has been approved as a rapid-acting antidepressant drug (RAAD). Although ketamine has an advantage over classic antidepressants (ADs) due to its rapid action, it remains a controversial drug due to its undesirable effects. Behavioral studies indicate that another enantiomer of ketamine, namely, (R)-ketamine, has been proposed as a safer but still effective RAAD. However, these conclusions have not been confirmed in any model of depression based on chronic environmental stress, which effectively reflects the core symptoms of this disease. Thus, we decided to compare the effects of (R)- and (S)-ketamine on chronic unpredictable mild stress (CUMS) in mice. Behavioral studies showed that (R)-ketamine induced anti-anhedonic and anti-apathetic efficacy up to seven days after administration, while the (S)-ketamine effect persisted up to 24 h or 3 days after injection. The behavioral effects of (R)-ketamine depended on the activation of TrkB receptors, while the (S)-ketamine effects did not. Western blot analyses showed that (S)-ketamine action might be related to both mTOR and ERK pathway activation and to the increased expression of GluA1 protein in the prefrontal cortex (PFC). In contrast, (R)-ketamine did not change ERK phosphorylation in the PFC, while it increased mTOR expression. (S)-Ketamine produced behavioral effects indicative of possible side effects in the dose range studied, while (R)-ketamine did not. This indicates that (R)-ketamine may be more effective, have a longer-lasting effect, and be safer to use than (S)-ketamine.

Scopolamine, a muscarinic cholinergic receptor antagonist, exerts fast and prolonged antidepressant effects in the clinic. In contrast, the current treatments for major depressive disorder (MDD) require long-term drug administration. On the other hand, the sole use of scopolamine might be related to the high risk of adverse effects. Therefore, it may be preferable to reduce its therapeutic dose. A new approach might include the co-administration of low-dose scopolamine with selected ligands of metabotropic glutamate (mGlu) receptors, which are known to possess antidepressant-like activity in several rodent tests and models of depression. The aim of the present study was to evaluate the potential antidepressant activity of low-dose scopolamine combined with an allosteric agonist of mGlu7 receptors, AMN082 in C57BL/6 mice. It was found that the combination of scopolamine (0.1 mg/kg) and AMN082 (1 mg/kg) exerted significant antidepressant-like effects in the tail suspension test (TST), but these effects were not observed in the mGlu7−/− mice. Furthermore, low-dose AMN082 co-administered with low-doses scopolamine (0.03 and 0.1 mg/kg) induced antidepressant-like activity in the forced swim test (FST) in mice. The tested compounds did not affect locomotor activity and did not impair spatial memory in the Morris water maze (MWM) test or motor coordination in the rotarod test. The results strongly indicated that there is an enhanced antidepressant-like action of scopolamine by AMN082. Co-administration of scopolamine with AMN082 might be a new strategy with better efficacy and a lower risk of adverse effects compared with the sole use of scopolamine or AMN082.

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.

Ketamine has been shown to induce a rapid antidepressant effect on patients with depression. In many animal models, both rapid and sustained antidepressant activities were also found in response to an antagonist of group II metabotropic glutamate receptors, LY341495, and its mechanism of action seemed to be similar in many ways to the action of ketamine. It has also been found that LY341495 enhanced the antidepressant-like activity of sub-effective doses of ketamine in rats without inducing adverse effects. Here, we investigated the role of AMPA receptor and TrkB receptor activation in the antidepressant-like effects of ketamine (3 mg/kg) co-administered with LY341495 (0.1 mg/kg), in the forced swim test in rats, at three time points (40 min, 3 h and 24 h) after joint administration of the tested compounds. It was found that the AMPA receptor antagonist NBQX (10 mg/kg) reversed the antidepressant effect of ketamine co-administered with LY341495 at all tested time points, whereas the TrkB receptor antagonist ANA-12 contributed to blockade of the effect of ketamine and LY341495 3 h after their joint administration. These results indicate that activation of AMPA receptor and BDNF-related signaling may play a role in the mechanism of antidepressant action of ketamine co-administered with LY341495.

Classic antidepressants that modulate monoaminergic systems are not sufficiently effective and require long systematic application. Recent studies suggest that substances that modulate glutamatergic system may produce an antidepressant effect which is not only faster but also more sustained.In this paper, the authors summarize the results of studies on antidepressant action of ketamine in patients with severe refractory depression, which have demonstrated high efficacy in a very short time after a single dose. Due to the adverse effects of ketamine that substantially exclude it from the daily use by patients, efforts have been made to find other NMDA receptor antagonists, which could mimic the therapeutic effect of ketamine but without the side effects. Intensive studies to elucidate ketamine's mechanism of antidepressant action have also been conducted. Herein, the results of research showing that metabotropic glutamate (mGlu) receptors could be the target of novel antidepressants are also presented.The intensive preclinical and clinical research on NMDA and mGlu receptor ligands, which is currently going on, could contribute to the awaited breakthrough in the field of novel antidepressant drug discovery. This line of research may also lead to a new understanding of the biological basis of depression.

The data concerning antipsychotic-like activity of negative allosteric modulators (NAMs)/antagonists of mGlu7 receptors are limited. The only available ligands for this receptor are MMPIP and ADX71743. In the present studies, we used stable cell line expressing mGlu7 receptor and it was shown that both compounds dose-dependently potentiated forskolin elevated cAMP concentration in the T-REx 293 cells, showing their inverse agonist properties. Subsequently, pharmacokinetic studies were performed. Both compounds were given intraperitoneally (i.p.) at the dose of 10 mg/kg and reached Cmax 0.25–0.5 h after administration, and then they declined rapidly, ADX71743 being almost undetectable 2 h after administration, while the concentration of MMPIP was still observed, suggesting that the concentration of MMPIP was more stable. Finally, we investigated the role of both mGlu7 receptor NAMs in animal models of schizophrenia. Behavioral tests commonly used in antipsychotic drug discovery were conducted. Both tested compounds dose-dependently inhibited MK-801-induced hyperactivity (MMPIP at 15 mg/kg; ADX at 5 and 15 mg/kg) and DOI-induced head twitches (MMPIP at 5, 10, 15 mg/kg; ADX at 2.5, 5, 10 mg/kg). Moreover, the same effects were noticed in novel object recognition test, where MMPIP (5, 10, 15 mg/kg) and ADX71743 (1, 5, 15 mg/kg) reversed MK-801-induced disturbances. In the social interaction test, antipsychotic activity was observed only for ADX71743 (5, 15 mg/kg). ADX71743 at the dose 2.5 mg/kg reversed MK-801-induced disruption in prepulse inhibition while MMPIP at 10 mg/kg reversed MK-801-induced disruption in spatial delayed alternation. The present studies showed that mGlu7 receptor may be considered as a putative target for antipsychotic drugs, though more studies are needed due to limited number of available ligands.

Over the past decade, ketamine has been one of the most commonly studied potential antidepressants. This is because it produces a spectacularly rapid and persistent therapeutic effect in people suffering from severe treatment-resistant depression (TRD), for which classical drugs are ineffective. Similar efficacy was demonstrated for scopolamine, a drug belonging to a completely different pharmacological group. This interesting coincidence piqued the interest of psychopharmacologists and prompted them to search for a possible common mechanism of these rapid acting antidepressant drugs (RAADs). A thorough explanation of this mechanism is also important because each of these substances induces serious side effects. Knowing the mechanism responsible for the therapeutic efficacy of RAADs could lead to minimizing, or even avoiding certain undesirable effects. This review provides an overview of the mechanism of action of a prototype RAAD, ketamine, in animal models, with a particular focus on the roles of NMDA receptors, AMPA receptors, synaptogenesis, and modulation of glutamate transmission by other modulators of this system, such as mGlu receptor ligands. Recently studied roles for ketamine enantiomers and metabolites in its rapid antidepressant effect are also considered. Finally, the results of multiple clinical trials are reported and discussed in relation to basic research. This review concludes that success in introducing novel therapeutic RAADs will depend on better cooperation and integration of neuroscience research and clinical practice.

Clinical studies have demonstrated rapid and long-lasting antidepressant effects of ketamine in depressive patients. It has been proposed that these effects are related to changes in synaptogenesis in the mechanism involving mammalian target of rapamycin (mTOR) activation. Similar mechanisms have been proposed for a group II metabotropic glutamate (mGlu) receptor antagonist, LY341495. We aimed to investigate whether other mGlu receptor ligands that produce antidepressant-like effects, namely, the mGlu5 antagonist MTEP and the mGlu7 agonist AMN082, induce the activation of mTOR signaling in the prefrontal cortex (PFC) in rats. AMN082 administered 60 min before the test increased the levels of pmTOR and pp70S6K, and the mTORC1 antagonist rapamycin reversed AMN082-induced changes in the forced swim test (FST) in rats. Furthermore, AMN082 administered 23 h before the decapitation of the rats increased the levels of synapsin I and GluR1, although it did not produce any effect in the FST at the same time point. However, MTEP induced a rapid but unsustained antidepressant-like effect, which was not related to the activation of the mTOR cascade. Finally, the antidepressant-like effects of MTEP or AMN082 were not antagonized by NBQX. In summary, the antidepressant-like activity of MTEP did not depend on the activation of mTOR signaling. However, we observed a unique feature of the mechanism of AMN082. The drug stimulated the mTOR signaling pathway and synaptic protein levels (like ketamine), while it did not induce a sustained antidepressant effect and its action was not directly dependent on AMPA receptor activation (as in classic antidepressants (ADs)).

Rationale Numerous preclinical and clinical studies have reported the rapid and sustained antidepressant effects of the NMDA receptor antagonist ketamine. Because ketamine induces several undesirable and dangerous effects, a variety of strategies have been suggested to avoid such effects. Objectives Here, we propose to enhance the sub-effective doses of ketamine by co-administration with the group II metabotropic glutamate (mGlu) receptor antagonist LY341495. This compound potentially acts as an antidepressant via a mechanism similar to that of ketamine. Methods To investigate the rapid and sustained antidepressant-like effects of these drugs, we administered ketamine and LY341495 individually or in combination, 40 min and 24 h before the forced swim test (FST). Results We found that sub-effective doses of ketamine and LY341495, given jointly, induce significant antidepressant-like effects, at both 40 min and 24 h after administration. The results obtained using Western blot technique indicate that mammalian target of rapamycin (mTOR) pathway activation may be involved in the mechanism of this action. The effects of drugs, used at identical ranges of times and doses, on spontaneous locomotor activity in rats were excluded. Furthermore, the results obtained from the rota-rod test and the ketamine-induced hyperlocomotion test suggest a lack of potentially adverse effects from the combined administration of ketamine and LY341495 at doses previously used in the FST. Conclusion Altogether, these data suggest that the joint administration of ketamine and LY341495 might be a noteworthy alternative to the use of solely ketamine in the therapy of depression.

Clinical studies have shown that the muscarinic receptor antagonist scopolamine induces a potent and rapid antidepressant effect relative to conventional antidepressants. However, potential undesirable effects, including memory impairment, partially limit the use of scopolamine in psychiatry. In the present study, we propose to overcome these limitations and enhance the therapeutic effects of scopolamine via administration in combination with the group II metabotropic glutamate (mGlu) receptor antagonist, LY341495. Joint administration of sub-effective doses of scopolamine (0.03 or 0.1 mg/kg, i.p.) with a sub-effective dose of LY341495 (0.1 mg/kg, i.p.) induced a profound antidepressant effect in the tail suspension test (TST) and in the forced swim test (FST) in mice. This drug combination did not impair memory, as measured using the Morris water maze (MWM), and did not influence the locomotor activity of mice. Furthermore, we found that an AMPA receptor antagonist, NBQX (10 mg/kg), completely reversed the antidepressant-like activity of a mixture of scopolamine and LY341495 in the TST. However, this effect was not influenced by para-chlorophenylalanine (PCPA) pre-treatment, indicating a lack of involvement of serotonergic system activation in the antidepressant-like effects of jointly given scopolamine and LY341495. Therefore, the combined administration of low doses of the antimuscarinic drug scopolamine and the group II mGlu receptor antagonist LY341495 might be a new, effective and safe strategy in the therapy of depression.

Earlier studies have demonstrated that the agonists of the mGlu 2/3 receptors produced anxiolytic actions after peripheral administration. However, the mechanism of their action is still not clear. Therefore the aim of the present study was to specify the role of the GABAergic and serotonergic system in the mechanism of the anxiolytic activity of group II mGlu receptor activators by using the stress induced hyperthermia test (SIH) in singly housed mice. We used an orthosteric mGlu 2/3 receptor agonist, LY379268, which induced anti-hyperthermic efficacy in the doses of 1–5 mg/kg (73% of inhibition after a highest dose). The effect of the second ligand used, a mGlu 2 receptor positive modulator (PAM), LY487379, was observed in a dose range of 0.5–5 mg/kg and reached 53% of the inhibition. The blockade of GABAergic system by GABA A receptor antagonist flumazenil (10 mg/kg) or GABA B receptor antagonist CGP55845 (10 mg/kg), and the blockade of serotonergic system by 5-HT 1A receptor antagonist WAY100635 (0.1 and 1 mg/kg) or 5-HT 2A/2C receptor antagonist ritanserin (0.5 mg/kg) had no influence on the anti-hyperthermic effect induced by effective dose of LY379268. However, the action of the effective dose of LY487379 was enhanced when co-administered with flumazenil, WAY100635 (0.1 mg/kg) and ritanserin. Similar results were observed for the subeffective dose of LY379268 (0.5 mg/kg). WAY100635 in a dose of 1 mg/kg did not induce any enhancing effect on the activity of compounds. Therefore, it seems that the antagonism towards GABA A receptors, presynaptic 5-HT 1A and postsynaptic 5-HT 2A/2C receptors is responsible for the phenomenon. This article is part of a Special Issue entitled ‘Anxiety and Depression’.

Our earlier studies have demonstrated that the non-selective group III mGlu receptor agonist, ACPT-I, produced anxiolytic rather than antidepressant-like actions after its peripheral administration. Here, we describe the effects of LSP1-2111 ((2S)-2-amino-4-[hydroxy[hydroxy(4-hydroxy-3-methoxy-5-nitro-phenyl)methyl]phosphoryl]butanoic acid), a novel orthosteric, preferential agonist of the mGlu4 receptor, a member of the group III mGlu receptors family, in the stress-induced hyperthermia (SIH) and elevated plus-maze (EPM) tests in mice. In both tests an anxiolytic-like effect was clearly seen in doses of 2 and 5 mg/kg, i.p. The compound did not produce antidepressant-like effects in the tail suspension test (TST) or in the forced swim test (FST) in mice. The potential anxiolytic effect of LSP1-2111 (5 mg/kg) in the SIH test was inhibited by the benzodiazepine receptor antagonist flumazenil (given i.p., 10 mg/kg), and by a 5-HT(1A) receptor antagonist N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl)cyclohexane-carboxamide (WAY100635) (0.1 mg/kg, s.c.). At the same time, ritanserin (0.5 mg/kg i.p.), the 5-HT(2A/C) receptor antagonist, did not change the anxiolytic-like effects of LSP1-2111. Moreover, the compound was not effective in 5-HT depleted animals. The results of these studies indicate that the GABAergic and serotonergic systems are involved in the potential anxiolytic action of LSP1-2111.