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Background: Muscarinic or 5-HT 1A receptors are crucial in learning and memory processes, and their expression is evident in the brain areas involved in cognition. The administration of the activators of these receptors prevents the development of cognitive dysfunctions in animal models of schizophrenia induced by MK-801 (N-methyl-d-aspartate receptor antagonist) administration. GABAergic dysfunction is considered as one of the most important causes of MK-801-induced spatial learning deficits., Methods: Novel object recognition (NOR) and Morris water maze (MWM) tests were used to study the anti-amnestic effect of the biased 5-HT 1A receptor agonist (F15599) alone or in combinations with VU0357017 (M 1 receptor allosteric agonist), VU0152100 (M 4 receptor positive allosteric modulator), and VU0238429 (M 5 receptor positive allosteric modulator) on MK-801-induced dysfunctions. The compounds were administered for 5 consecutive days. Animals tested with the MWM underwent 5-day training. Western blotting was used to study the expressions of 5-HT 1A receptors and the level of GAD 65 in the frontal cortices (FCs) and hippocampi of the animals., Results: F15599 prevented the amnestic effect induced by MK-801 in the MWM at a dose of 0.1 mg/kg. The co-administration of the compound with muscarinic receptors activators had no synergistic effect. The additive effect of the combinations was evident in the prevention of declarative memory dysfunctions investigated in NOR. The administration of MK-801 impaired 5-HT 1A expression in the hippocampi and decreased GAD 65 levels in both the FCs and hippocampi. The administration of muscarinic ligands prevented these MK-801-induced deficits only in the hippocampi of MWM-trained animals. No effects of the compounds were observed in untrained mice., Conclusion: Our results indicate that F15599 prevents schizophrenia-related spatial learning deficits in the MWM; however, the activity of the compound is not intensified with muscarinic receptors activators. In contrast, the combined administration of the ligands is effective in the NOR model of declarative memory. The muscarinic receptors activators reversed MK-801-induced 5-HT 1A and GAD 65 dysfunctions in the hippocampi of MWM-trained mice, but not in untrained mice., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The mGlu 7 receptor belongs to the III group of metabotropic glutamatergic (mGlu) receptors and physiologically serves as an "emergency" receptor that is activated by high, almost pathological, glutamate concentrations. Of all mGlu receptors, this receptor is most highly expressed in the brain. Additionally, relatively intense expression of the receptor was found at the periphery, for example in the bowels or in the reproductive system of male mice, but this review will be focused predominantly on its role in the brain. In the CNS, the receptor is expressed presynaptically, in the center of the synaptic cleft, at the terminals of both excitatory glutamatergic and inhibitory GABAergic neurons. Thus, it may regulate the release of both glutamate and GABA. Schizophrenia is thought to develop as a consequence of a disturbed glutamatergic-GABAergic balance in different parts of the brain. Thus, the mGlu 7 receptor may be involved in the pathophysiology of schizophrenia and consequently constitute the target for antipsychotic drug discovery. In this review, we summarize the available data about mGlu 7 receptor ligands and their activity in animal models of schizophrenia. At present, only a few ligands are available, and negative allosteric modulators (NAMs) appear to exert antipsychotic-like efficacy, indicating that the inhibition of the receptor could constitute a promising target in the search for novel drugs. Additionally, the data concerning the expression of the receptor in the CNS and putative mechanisms by which its inhibition may contribute to the treatment of schizophrenia will be discussed. Finally, the polymorphisms of genes encoding the receptor in schizophrenic patients will also be provided., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Nitric oxide is a small gaseous molecule that plays important roles in the majority of biological functions. Impairments of NO-related pathways contribute to the majority of neurological disorders, such as Alzheimer's disease (AD), and mental disorders, such as schizophrenia. Cognitive decline is one of the most serious impairments accompanying both AD and schizophrenia. In the present study, the activities of NO donors, slow (spermine NONOate) or fast (DETANONOate) releasers, and selective inhibitor of neuronal nitric oxide synthase N(ω)-propyl-l-arginine (NPLA) were investigated in pharmacological models of schizophrenia and AD. Cognitive impairments were induced by administration of MK-801 or scopolamine and were measured in novel object recognition (NOR) and Y-maze tests. The compounds were investigated at doses of 0.05-0.5 mg/kg. The dose-dependent effectiveness of all the compounds was observed in the NOR test, while only the highest doses of spermine NONOate and NPLA were active in the Y-maze test. DETANONOate was not active in the Y-maze test. The impact of the investigated compounds on motor coordination was tested at doses of 0.5 and 1 mg/kg. Only NPLA at a dose of 1 mg/kg slightly disturbed motor coordination in animals., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Over the past 20 years, converging lines of evidence have both linked glutamatergic dysfunction to the pathophysiology of depression and demonstrated that the glutamatergic synapse presents multiple targets for developing novel antidepressants. The robust antidepressant effects of the N-methyl-D-aspartate receptor antagonists ketamine and traxoprodil provide target validation for this family of ionotropic glutamate receptors. This article reviews the preclinical evidence that it may be possible to develop glutamate-based antidepressants by not only modulating ionotropic (N-methyl-D-aspartate and alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid) and metabotropic glutamate (mGlu) receptors, including mGlu2/3, mGLu5 and mGlu7 receptors, but also by altering synaptic concentrations of glutamate via specialized transporters such as glial glutamate transporter 1 (excitatory amino-acid transporter 2)., (Copyright © 2013 Society of Biological Psychiatry. All rights reserved.)

Corticotropin releasing factor (CRF) is a neuropeptide widely distributed in the brain. The role of CRF in the behavioural activity and modulation of anxiety states in several brain structures has been well documented, but its function in the cerebral cortex still remains unknown. The aim of our study was to investigate the effect of CRF injected bilaterally into rat frontal cortex on the locomotor and exploratory activity and anxiety of rats. We also examined the effect of CRF on extracellularly recorded field potentials in rat frontal cortical slices in vitro. Behavioural experiments showed that CRF in doses of 0.05, 0.1, 0.2 microg/1 microl/site decreased locomotor and exploratory activity during a 40-min session in the open field test. In the elevated plus-maze test, CRF in a dose of 0.2 microg/1 microl/site produced a significant anxiolytic-like effect, which was prevented by CRF receptor antagonists (alpha-helicalCRF(9-41) and NBI 27914). Electrophysiological experiments showed that CRF-induced a transient depression of field potentials in slices partly disinhibited by GABA(A) and GABA(B) receptors antagonists. The blockade of NMDA receptors prevented the occurrence of that effect. The obtained results suggest that CRF may have anxiolytic-like effects in the frontal cortex. Moreover, the peptide inhibits locomotor and exploratory activity and depresses excitatory synaptic transmission in a NMDA receptor-dependent manner.

The involvement of glutamate in the pathophysiology of depression has been suggested by a number of experiments. It was well established that compounds, which decreased glutamatergic transmission via blockade of NMDA receptor, produced antidepressant-like action in animal tests and models. The present study was carried out to investigate whether a selective mGluR5 antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine (MTEP) induces antidepressant-like effects after intraperitoneal injections in male Wistar rats or male C57BL/6J mice. Potential antidepressant-like activity of MTEP was evaluated using the forced swimming test (FST) in rats, the tail suspension test (TST) in mice and the olfactory bulbectomy (OB) model of depression in rats. The results of our studies showed, that MTEP (0.3-3 mg/kg) produced a significant dose-dependent decrease in the immobility time of mice in the TST, however, at doses of 1 or 10 mg/kg, it did not influence the behavior of rats in the FST in rats. Moreover, the repeated administration of MTEP (1 mg/kg) attenuated the OB-related hyperactivity of rats in the open field test, in the manner similar to that seen following chronic (but not acute) treatment with typical antidepressant drugs. These data suggest that MTEP, which is considered to be a potential therapeutic agent, may play a role in the therapy of depression.

Amygdala is the brain structure responsible for integrating all behavior connected with fear, and in this structure two neuropeptides, neuropeptide Y (NPY), corticoliberin (CRF) and the most abundant excitatory neurotransmitter glutamate seem to take part in the regulation of anxiety behavior. Our previous studies showed the modulation of NPY and CRF expression by classical neurotransmitters in some brain structures, therefore in the present study we investigated the effect of NMDA receptor antagonists on the expression of NPY and CRF immunoreactivity in the rat brain amygdala. A non-competitive NMDA receptor antagonist, MK-801, or a functional NMDA antagonist, ACPC were used. Brains were taken out and processed by immunohistochemical method using specific NPY or CRF antibodies. The staining intensity and density of IR neurons were evaluated under a microscope in amygdala sections. It was found that both MK-801 and ACPC induced a significant decrease in NPY-immunoreactivity in amygdala nerve cell bodies and terminals, which may suggest an increased release of this peptide. CRF-IR was decreased after ACPC only. The obtained results indicate that in the amygdala, the NMDA receptors mediated glutamatergic transmission may regulate NPY neurons., (Copyright 2001 Harcourt Publishers Ltd.)