Depression-like effects induced by chronic unpredictable mild stress in mice are rapidly reversed by a partial negative allosteric modulator of mGlu receptor, M-5MPEP.

Rationale: Due to the numerous limitations of ketamine as a rapid-acting antidepressant drug (RAAD), research is still being conducted to find an effective and safe alternative to this drug. Recent studies indicate that the partial mGlu receptor negative allosteric modulator (NAM), 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP), has therapeutic potential as an antidepressant.

Objectives: The study aimed to investigate the potential rapid antidepressant-like effect of M-5MPEP in a mouse model of depression and to determine the mechanism of this action.

Subchronic administration of scopolamine reverses UCMS-induced behavior in mice via eEF2 protein dephosphorylation.

Background: The cholinergic system has been increasingly linked to the pathophysiology of mood disorders such as depression, with the potential involvement of nicotinic and/or muscarinic receptors. Conventional antidepressants usually require weeks of daily dosing to achieve a full antidepressant response. In contrast, clinical studies have shown that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, can induce potent and rapid antidepressant effects, requiring only a few days of treatment.

Partial mGlu receptor NAM, M-5MPEP, induces rapid and sustained antidepressant-like effects in the BDNF-dependent mechanism and enhances (R)-ketamine action in mice.

Background: Partial negative allosteric modulators (NAM) of the metabotropic glutamate 5 (mGlu) receptor are an excellent alternative to full antagonists and NAMs because they retain therapeutic effects and have a much broader therapeutic window. Here, we investigated whether partial mGlu NAM, 2-(2-(3-methoxyphenyl)ethynyl)-5-methylpyridine (M-5MPEP), induced a fast and sustained antidepressant-like effect, characteristic of rapid-acting antidepressant drugs (RAADs) like ketamine, in mice.

Methods: A tail suspension test (TST) was used to investigate acute antidepressant-like effects.

Prevention of MK-801-induced amnestic effect with combined activation of 5-HT and muscarinic receptors in mice.

Background: Muscarinic or 5-HT 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.

TC-G 1008 facilitates epileptogenesis by acting selectively at the GPR39 receptor but non-selectively activates CREB in the hippocampus of pentylenetetrazole-kindled mice.

The pharmacological activation of the GPR39 receptor has been proposed as a novel strategy for treating seizures; however, this hypothesis has not been verified experimentally. TC-G 1008 is a small molecule agonist increasingly used to study GPR39 receptor function but has not been validated using gene knockout. Our aim was to assess whether TC-G 1008 produces anti-seizure/anti-epileptogenic effects in vivo and whether the effects are mediated by GPR39.

The Antidepressant-like Activity and Cognitive Enhancing Effects of the Combined Administration of ()-Ketamine and LY341495 in the CUMS Model of Depression in Mice Are Related to the Modulation of Excitatory Synaptic Transmission and LTP in the PFC.

()-Ketamine is the first rapid-acting antidepressant drug (RAAD) introduced for the treatment of depression. However, research is still being carried out on the search for further RAADs that will be not only effective but also safe to use. Recent data have indicated that the combined administration of ()-ketamine and the mGlu receptor antagonist LY341495 (mixRL) induces rapid and sustained effects in the chronic unpredictable mild stress (CUMS) model of depression in mice, and the use of this drug combination is associated with a low risk of undesirable effects.

Zinc Deficiency Blunts the Effectiveness of Antidepressants in the Olfactory Bulbectomy Model of Depression in Rats.

Currently used antidepressants do not always provide the desired results, and many patients suffer from treatment-resistant depression. Clinical studies suggest that zinc deficiency (ZnD) may be an important risk factor for depression and might blunt the effect of antidepressants. This study aimed to examine whether ZnD might blunt the effectiveness of antidepressants in the olfactory bulbectomy model (OB) of depression in rats.

Combined Administration of ()-Ketamine and the mGlu2/3 Receptor Antagonist LY341495 Induces Rapid and Sustained Effects in the CUMS Model of Depression via a TrkB/BDNF-Dependent Mechanism.

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 (()-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.

The effectiveness of (R)-ketamine and its mechanism of action differ from those of (S)-ketamine in a chronic unpredictable mild stress model of depression in C57BL/6J mice.

(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.

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.

Imipramine Influences Body Distribution of Supplemental Zinc Which May Enhance Antidepressant Action.

Zinc (Zn) was found to enhance the antidepressant efficacy of imipramine (IMI) in human depression and animal tests/models of depression. However, the underlying mechanism for this effect remains unknown. We measured the effect of intragastric () combined administration of IMI (60 mg/kg) and Zn (40 mg Zn/kg) in the forced swim test (FST) in mice.

Ketamine and Ro 25-6981 Reverse Behavioral Abnormalities in Rats Subjected to Dietary Zinc Restriction.

Clinical and preclinical studies indicate that zinc (Zn) is an essential factor in the development and treatment of major depressive disorder (MDD). Conventional monoamine-based antidepressants mobilize zinc in the blood and brain of depressed patients as well as rodents. N-methyl-D-aspartate acid receptor (NMDAR) antagonists exhibit antidepressant-like activity.

The influence of the duration of chronic unpredictable mild stress on the behavioural responses of C57BL/6J mice.

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.

Antidepressant-like activity of hyperforin and changes in BDNF and zinc levels in mice exposed to chronic unpredictable mild stress.

Chronic unpredictable mild stress (CUMS) - a rodent model of depression mimics a variety of neurochemical and behavioral alterations similar to those seen in human depression. This study evaluated the antidepressant activity of hyperforin in the CUMS model using fluoxetine (FLX) as a reference drug. The antidepressant-like effects of hyperforin and FLX were evaluated in the tail suspension test (TST), forced swim test (FST), and splash test (SPT).

Hyperforin Potentiates Antidepressant-Like Activity of Lanicemine in Mice.

N-methyl-D-aspartate receptor (NMDAR) modulators induce rapid and sustained antidepressant like-activity in rodents through a molecular mechanism of action that involves the activation of Ca dependent signaling pathways. Moreover, ketamine, a global NMDAR antagonist is a potent, novel, and atypical drug that has been successfully used to treat major depressive disorder (MDD). However, because ketamine evokes unwanted side effects, alternative strategies have been developed for the treatment of depression.

Involvement of extracellular signal-regulated kinase (ERK) in the short and long-lasting antidepressant-like activity of NMDA receptor antagonists (zinc and Ro 25-6981) in the forced swim test in rats.

Short and long acting NMDA receptor (NMDAR) antagonists exert their antidepressant-like effects by activating signaling pathways involved in the synthesis of synaptic proteins and formation of new synaptic connections in the prefrontal cortex (PFC) of rats. The blockade of the ERK pathway abolishes ketamine and Ro 25-6981 antidepressant potency. However, the role of ERK in the antidepressant-like activity of short acting NMDAR antagonists is still unclear.