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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 ((R)-ketamine) or mGlu2/3 receptor antagonists, which induce ketamine-like effects and enhance its action. Here, we propose combining these two strategies to investigate the antidepressant-like effects of low doses of two ketamine enantiomers in combination with a low dose of the mGlu2/3 receptor antagonist LY341495. Rapid and sustained antidepressant-like effects were assessed in C57BL/6J mice using the tail suspension test (TST) and the chronic unpredictable mild stress (CUMS) model of depression in stress-naïve mice. ELISA was used to measure BDNF levels. In the TST, low doses of both (S)-ketamine and (R)-ketamine were potentiated by a subeffective dose of LY341495. However, in the CUMS model, only (R)-ketamine was able to induce long-lasting anti-apathetic and anti-anhedonic effects when coadministered with low-dose LY341495. The mechanism of this drug combination was dependent on BDNF and AMPA receptor activity. ELISA results suggest that the hippocampus might be the site of this action. MGlu2/3 receptor antagonists, in combination with (R)-ketamine, may serve as potential RAADs, with a high efficiency and low risk of side effects.

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.

MK-801, an NMDA receptor antagonist, and scopolamine, a cholinergic receptor blocker, are widely used as tool compounds to induce learning and memory deficits in animal models to study schizophrenia or Alzheimer-type dementia (AD), respectively. Memory impairments are observed after either acute or chronic administration of either compound. The present experiments were performed to study the nitric oxide (NO)-related mechanisms underlying memory dysfunction induced by acute or chronic (14 days) administration of MK-801 (0.3 mg/kg, i.p.) or scopolamine (1 mg/kg, i.p.). The levels of L-arginine and its derivatives, L-citrulline, L-glutamate, L-glutamine and L-ornithine, were measured. The expression of constitutive nitric oxide synthases (cNOS), dimethylaminohydrolase (DDAH1) and protein arginine N-methyltransferases (PMRTs) 1 and 5 was evaluated, and the impact of the studied tool compounds on cGMP production and NMDA receptors was measured. The studies were performed in both the cortex and hippocampus of mice. S-nitrosylation of selected proteins, such as GLT-1, APP and tau, was also investigated. Our results indicate that the availability of L-arginine decreased after chronic administration of MK-801 or scopolamine, as both the amino acid itself as well as its level in proportion to its derivatives (SDMA and NMMA) were decreased. Additionally, among all three methylamines, SDMA was the most abundant in the brain (~70%). Administration of either compound impaired eNOS-derived NO production, increasing the monomer levels, and had no significant impact on nNOS. Both compounds elevated DDAH1 expression, and slight decreases in PMRT1 and PMRT5 in the cortex after scopolamine (acute) and MK-801 (chronic) administration were observed in the PFC, respectively. Administration of MK-801 induced a decrease in the cGMP level in the hippocampus, accompanied by decreased NMDA expression, while increased cGMP production and decreased NMDA receptor expression were observed after scopolamine administration. Chronic MK-801 and scopolamine administration affected S-nitrosylation of GLT-1 transport protein. Our results indicate that the analyzed tool compounds used in pharmacological models of schizophrenia or AD induce changes in NO-related pathways in the brain structures involved in cognition. To some extent, the changes resemble those observed in human samples.

Considering the allosteric regulation of mGlu receptors for potential therapeutic applications, we developed a group of 1,2,4-oxadiazole derivatives that displayed mGlu 4 receptor positive allosteric modulatory activity (EC 50 = 282-656 nM). Selectivity screening revealed that they were devoid of activity at mGlu 1 , mGlu 2 and mGlu 5 receptors, but modulated mGlu 7 and mGlu 8 receptors, thus were classified as group III-preferring mGlu receptor agents. None of the compounds was active towards hERG channels or in the mini-AMES test. The most potent in vitro mGlu 4 PAM derivative 52 (N-(3-chloro-4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)picolinamide) was readily absorbed after i.p. administration (male Albino Swiss mice) and reached a maximum brain concentration of 949.76 ng/mL. Five modulators (34, 37, 52, 60 and 62) demonstrated significant anxiolytic- and antipsychotic-like properties in the SIH and DOI-induced head twitch test, respectively. Promising data were obtained, especially for N-(4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)picolinamide (62), whose effects in the DOI-induced head twitch test were comparable to those of clozapine and better than those reported for the selective mGlu 4 PAM ADX88178.

The data concerning antipsychotic-like activity of negative allosteric modulators/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 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 ligands may be considered as a target for antipsychotic drugs, even though more studies are needed due to limited number of available ligands.

Rationale Several studies have suggested that modulation of the glutamatergic system could be a new, efficient way to achieve antidepressant activity. Behavioral data showed that group II mGlu receptor antagonists (i.e., (1 R , 2 R , 3 R , 5 R , 6 R )-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (MGS0039) and (2 S )-2-amino-2-[(1 S ,2 S )-2-carboxycycloprop-1- yl ]-3-(xan th -9- yl ) propanoic acid (LY341495)) elicited antidepressant activity in several animal models of depression in rats and/or mice. Although the antidepressant-like activity of MGS0039 and LY341495 is well documented, the mechanism of the antidepressant action of these compounds is still not clear. Objectives The aim of the present study was to specify the role of the serotonergic system in the mechanism of the antidepressant-like activity of group II mGlu receptor ligands by using the tail suspension test (TST) in mice; the role of AMPA receptors was also investigated. Furthermore, the possible antidepressant-like action of MGS0039 using the olfactory bulbectomy (OB) model of depression in rats was investigated. Results The results of the TST studies showed that antidepressant-like action of group II mGlu receptor antagonists does not depend on serotonergic system activation. However, the AMPA receptor seems to play a key role in the antidepressant-like action of these compounds. Moreover, we have shown that repeated administration of MGS0039 attenuated OB-related deficits, confirming antidepressant-like activity of the tested compound. Conclusions The results suggest that the blockade of group II mGlu receptors may be effective in the treatment of depression. Moreover, we have found that the mechanism of action of group II mGlu receptor antagonists differs from that of typical antidepressants, such as SSRIs.

Following the glutamatergic theory of schizophrenia and based on our previous study regarding the antipsychotic-like activity of mGlu7 NAMs, we synthesized a new compound library containing 103 members, which were examined for NAM mGlu7 activity in the T-REx 293 cell line expressing a recombinant human mGlu7 receptor. Out of the twenty-two scaffolds examined, active compounds were found only within the quinazolinone chemotype. 2-(2-Chlorophenyl)-6-(2,3-dimethoxyphenyl)-3-methylquinazolin-4(3H)-one (A9-7, ALX-171, mGlu7 IC50 = 6.14 µM) was selective over other group III mGlu receptors (mGlu4 and mGlu8), exhibited satisfactory drug-like properties in preliminary DMPK profiling, and was further tested in animal models of antipsychotic-like activity, assessing the positive, negative, and cognitive symptoms. ALX-171 reversed DOI-induced head twitches and MK-801-induced disruptions of social interactions or cognition in the novel object recognition test and spatial delayed alternation test. On the other hand, the efficacy of the compound was not observed in the MK-801-induced hyperactivity test or prepulse inhibition. In summary, the observed antipsychotic activity profile of ALX-171 justifies the further development of the group of quinazolin-4-one derivatives in the search for a new drug candidate for schizophrenia treatment.

This study was designed to determine the characteristics of tumour cell-derived microvesicles (TMV) and their interactions with human monocytes. TMV were shed spontaneously by three different human cancer cell lines but their release was significantly increased upon activation of the cells with phorbol 12-myristate 13-acetate (PMA). TMV showed the presence of several surface determinants of tumour cells, e.g. HLA class I, CD29, CD44v7/8, CD51, chemokine receptors (CCR6, CX3CR1), extracellular matrix metalloproteinase inducer (EMMPRIN), epithelial cell adhesion molecule (EpCAM), but their level of expression differed from that on cells they originated from. TMV also carried mRNA for growth factors: vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), interleukin-8 (IL-8) and surface determinants (CD44H). TMV were localized at the monocytes surface following their short exposure to TMV, while at later times intracellularly. TMV transferred CCR6 and CD44v7/8 to monocytes, exerted antiapoptotic effect on monocytes and activated AKT kinase (Protein Kinase B). Thus, TMV interact with monocytes, alter their immunophenotype and biological activity. This implicates the novel mechanism by which tumour infiltrating macrophages may be affected by tumour cells not only by a direct cell to cell contact, soluble factors but also by TMV.

Rationale Numerous studies indicate the potential antidepressant actions of several mGlu5 receptor antagonists, including 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP). The explanation for the mechanism of these effects might be a key step in finding new antidepressant drugs (AD). Objectives The aim of the present study was to investigate the possible role of the serotonergic system in the antidepressant-like activity of MTEP in the tail suspension test (TST) in C57BL/6J mice, using selected antagonists of serotonergic receptors and by applying two different methods of serotonin (5-HT) depletion. Results The results of our studies showed that the mGlu5 receptor antagonist, MTEP, similar to the fluoxetine used as reference AD, did not induce antidepressant-like effects in mice pretreated with tryptophan hydroxylase inhibitor, para -chlorophenylalanine. On the other hand, MTEP worked as a potential AD in the TST in mice fed on a tryptophan-free (TRP-free) diet for 3 weeks. However, fluoxetine, which was used as a reference control was also active in this experiment, suggesting that a TRP-free diet was not sufficiently effective in reducing the 5-HT level. Furthermore, we showed that the 5HT2A/2C antagonist, ritanserin, yet not the 5-HT1A antagonist, WAY100635, 5HT1B antagonist, SB224289 or 5HT4 antagonist, GR125487, reversed the antidepressant-like effects of MTEP in the TST. Finally, a sub-effective dose of MTEP co-administered with a sub-effective dose of citalopram induced an antidepressant-like effect in the TST in mice. Conclusion The results of our studies suggest the involvement of serotonergic system activation in the antidepressant-like effects of the mGlu5 antagonist, MTEP, in the TST in mice.

Several lines of evidence indicate that inhibition of the metabotropic glutamate (mGlu) receptor 5 produces anxiolytic-like effects in rodents. Peptide neurotransmitter neuropeptide Y (NPY) produces an anxiolytic effect in rats after intraventricular or intra-amygdalar administration. Many classes of anxiolytic drugs exert their effect through the GABA–benzodiazepine (BZD) receptor complex. Therefore, in the present study we have investigated whether the anxiolytic action of MPEP (2-methyl-6-(phenylethynyl)pyridyne), an mGlu5 receptor antagonist, is mediated by a mechanism involving either the GABA–BZD receptor complex or NPY receptor. In the behavioral studies, the anxiolytic activity of MPEP (10 mg/kg, i.p.) was examined using plus-maze test. The BZD antagonist flumazenil (10 mg/kg, i.p.) was given to one group of rats and Y1 receptor antagonist BIBO 3304 (((R)- N -[[4-(aminocarbonylaminomethyl) phenyl] methyl]-N2-(diphenylacetyl)-argininamide trifluoroacetate)3304) (200 pmol/site, intra-amygdala) to the other. It was found that anxiolytic effects of MPEP were not changed by flumazenil, but were abolished by BIBO 3304. Immunohistochemical studies showed a high density of mGlu5 receptor immunoreactivity (IR) in the amygdala. The effect of MPEP on NPY expression in the amygdala was studied using immunohistochemistry (IH) and radioimmunoassay (RIA). Both methods showed a diminution of NPY IR expression, to about 43% (IH) or 81% (RIA) of the control level after multiple administrations, but we observed an increase up to 148% of the control after single MPEP administration. These effects may suggest a release of NPY from nerve terminals after MPEP administration. Our results indicate that the anxiolytic action of MPEP is conveyed through NPY neurons with the involvement of Y1 receptors in the amygdala and that BZD receptors do not significantly contribute to these effects.