Ketamine and Ro 25-6981 reverse behaviorala 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. However, not much is known about the antidepressant efficacy of NMDAR antagonists in zinc-deficient (ZnD) animals. We evaluated the antidepressant-like activity of two NMDAR antagonists (ketamine; global NMDAR antagonist and Ro 25-6981 (Ro); selective antagonist of the GluN2B NMDAR subunit) in ZnD rats using the forced swim test (FST) and sucrose intake test (SIT). A single dose of either Ro 25-6981 or ketamine normalized depressive-like behaviors in ZnD rats; however, Ro was effective in both tests, while ketamine was only effective in the FST. Additionally, we investigated the mechanism of antidepressant action of Ro at the molecular (analysis of protein expression by Western blotting) and anatomical (density of dendritic spines by Golgi Cox-staining) levels. ZnD rats exhibited decreased phosphorylation of the p70S6K protein, and enhanced density of dendritic spines in the prefrontal cortex (PFC) compared to control rats. The antidepressant-like activity of Ro was associated with the increased phosphorylation of p70S6K and ERK in the PFC. In summary, single doses of the NMDAR antagonists ketamine and Ro exhibited antidepressant-like activity in the ZnD animal model of depression. Animals were only deprived of Zn for 4 weeks and the biochemical effects of Zn deprivation and Ro were investigated in the PFC and hippocampus. The shorter duration of dietary Zn restriction may be a limitation of the study. However, future studies with longer durations of dietary Zn restriction, as well as the investigation of multiple brain structures, are encouraged as a supplement to this study

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 (p.o.) combined administration of IMI (60 mg/kg) and Zn (40 mg Zn/kg) in the forced swim test (FST) in mice. The effect of Zn + IMI on serum, brain, and intestinal Zn concentrations; Zn transporter (ZnT, ZIP) protein levels in the intestine and ZnT in the brain; including BDNF (brain-derived neurotrophic factor) and CREB (cAMP response element-binding protein) protein levels in the brain were evaluated. Finally, the effect of IMI on Zn permeability was measured in vitro in colon epithelial Caco-2 cells. The co-administration of IMI and Zn induced antidepressant-like activity in the FST in mice compared to controls and Zn or IMI given alone. This effect correlated with increased BDNF and the ratio of pCREB/CREB protein levels in the prefrontal cortex (PFC) compared to the control group. Zn + IMI co-treatment increased Zn concentrations in the serum and brain compared to the control group. However, in serum, co-administration of IMI and Zn decreased Zn concentration compared to Zn alone treatment. Also, there was a reduction in the Zn-induced enhancement of ZnT1 protein level in the small intestine. Zn + IMI also induced an increase in the ZnT4 protein level in the PFC compared to the control group and normalized the Zn-induced decrease in the ZnT1 protein level in the hippocampus (Hp). The in vitro studies revealed enhanced Zn permeability (observed as the increased transfer of Zn through the intestinal cell membrane) after IMI treatment. Our data indicate that IMI enhances Zn transfer through the intestinal tract and influences the redistribution of Zn between the blood and brain. These mechanisms might explain the enhanced antidepressant efficacy of combined IMI/Zn treatment observed in the FST in mice

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 Ca2+ 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. The objective of the present study was to determine the antidepressant effects of either a single dose of hyperforin or lanicemine vs. their combined effects in mice. Hyperforin modulates intracellular Ca2+ levels by activating Ca2+-conducting non-selective canonical transient receptor potential 6 channel (TRPC6) channels. Lanicemine, on the other hand, blocks NMDARs and regulates Ca2+ dependent processes. To evaluate the antidepressant-like activity of hyperforin and lanicemine, a set of in vivo (behavioral) and in vitro methods (western blotting, Ca2+ imaging studies, electrophysiological, and radioligand binding assays) was employed. Combined administration of hyperforin and lanicemine evoked long-lasting antidepressant-like effects in both naïve and chronic corticosterone-treated mice while also enhancing the expression of the synapsin I, GluA1 subunit, and brain derived neurotrophic factor (BDNF) proteins in the frontal cortex. In Ca2+ imaging studies, lanicemine enhanced Ca2+ influx induced by hyperforin. Moreover, compound such as MK-2206 (Akt kinase inhibitor) inhibited the antidepressant-like activity of hyperforin in the tail suspension test (TST). Hyperforin reversed disturbances induced by MK-801 in the novel object recognition (NOR) test and had no effects on NMDA currents and binding to NMDAR. Our results suggest that co-administration of hyperforin and lanicemine induces long-lasting antidepressant effects in mice and that both substances may have different molecular targets

Research NCAM protein levels in the prefrontal cortex of rats in some models of depression

Depresja, na którą cierpi około 121 mln ludzi na świecie, jest jednym z najczęściej występujących schorzeń psychicznych. Stosowane obecnie leki przeciwdepresyjne wykazują niską skuteczność i wywołują wiele działań niepożądanych, dlatego potrzebne są nowe strategie terapeutyczne. Wiele uwagi poświęca się również poszukiwaniu specyficznych markerów depresji. Jednym z nich jest białko adhezyjne NCAM należące do nadrodziny białek immunoglobulinowych. NCAM jest związany z funkcjami serotoninergicznymi i neurotroficznymi w korze przedczołowej.Celem niniejszej pracy było zbadanie poziomu białka NCAM w korze przedczołowej w modelu chronicznego łagodnego stresu (CMS) oraz w modelu usunięcia opuszek węchowych (OB) oraz po chronicznych podaniach leków przeciwdepresyjnych (imipramina, dezipramina). Badania wykonano przy zastosowaniu metody Western Blot.W grupie zwierząt, które zostały poddane procedurze łagodnego chronicznego stresu zaobserwowano statystycznie istotnie podwyższony poziom NCAM w korze przedczołowej w porównaniu do zwierząt kontrolnych. Chroniczne podanie imipraminy w dawce 10mg/kg wpłynęły na obniżenie poziomu NCAM u tych zwierząt. W modelu usunięcia opuszek węchowych zaobserwowano natomiast znacznie zmniejszony poziom NCAM w korze przedczołowej szczurów z usuniętymi opuszkami,a wielokrotne podania dezipraminy w dawce 10mg/kg wpłynęło na wzrost białka adhezyjnego NCAM w badanej strukturze. Wyniki przeprowadzonych badań wskazują na istotną rolę białka NCAM w mechanizmach powstawania depresji. Zaobserwowane różnice pomiędzy poziomami NCAM w chronicznym łagodnym stresie i modelu usunięcia opuszek węchowych sugerują, że zmiany w poziomie NCAM mogą się różnić w zależności od rodzaju czynników wywołujących depresję. Szczególnie istotne znaczenie może nabrać to białko adhezyjne w aspekcie zastosowania nowych leków przeciwdepresyjnych, których mechanizm działania byłby związany z przebudową mechanizmów neuronowych w które zaangażowane jest to białko.Depression, which affects about 121 million people worldwide, is one of the most common mental illnesses. Unfortunately, current drug therapies for depression are not always effective and may cause a variety of adverse effects. Thus, there is a need for novel antidepressant therapies. Very important aspect in the context of depression is the lack of specific and sensitive biomarkers. One of the protein that is suggested as a marker of depression is the adhesion protein NCAM, belonging to immunoglobulin superfamily of proteins. NCAM is associated with serotonergic and neurotrophic functions in the prefrontal cortex. The aim of this study was to examine the level of NCAM protein in the prefrontal cortex in the chronic mild stress and the olfactory bulbectomy models of depression and after chronic treatment of antidepressants (imipramine, desipramine). Studies were made using the method of Western Blot.In the case of chronic mild stress the increased level of NCAM was found in the stressed group as compared to control group. Chronic administration of imipramine at a dose of 10 mg/kg resulted in lowering levels of NCAM. In the olfactory bulbectomy model of depression, removal of the olfactory bulbs decreased level of NCAM and repeated administration of desipramine at a dose of 10mg/kg resulted in an increase in NCAM adhesion proteins level.Results of this study indicate the importance of NCAM protein in the mechanisms of pathophysiology of depression. The differences observed between the levels of NCAM in chronic mild stress and olfactory bulbectomy suggests that changes in the level of NCAM can vary depending on factors causing depression. Of particular importance may become the adhesion protein in the context of the search for a new antidepressant drugs whose mechanism of action would be associated with the reconstruction of the neural mechanisms that involve this protein

The Antidepressant-like Activity and Cognitive Enhancing Effects of the Combined Administration of (<i>R</i>)-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

(S)-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 (R)-ketamine and the mGlu2/3 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. Considering the possible influence of stress on cortical plasticity and, on the other hand, the role of this plasticity in the mechanism of action of ketamine, we decided to investigate whether mixed RL affects synaptic plasticity in the prefrontal cortex (PFC) in the CUMS model of depression using electrophysiological techniques and explore whether these effects are related to memory impairments. Using behavioral methods, we found that a single administration of mixRL reversed CUMS-induced PFC-dependent memory deficits and alleviated depression-like effects induced by CUMS. In turn, electrophysiological experiments indicated that the amplitude of field potentials as well as paired-pulse responses in CUMS mice were increased, and mixRL was found to reverse these effects. Additionally, the magnitude of long-term potentiation (LTP) was reduced in CUMS mice, and mixRL was shown to restore this parameter. In summary, mixRL appeared to exert its antidepressant effects and cognitive enhancing effects in a mouse model of depression, at least in part, by mechanisms involving modulation of glutamatergic transmission and LTP in the PFC

Combined Administration of (R)-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 ((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-na&iuml;ve 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

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. For this purpose, rats were subjected to the OB model, fed a zinc-deficient diet (3 mg Zn/kg) for 3 weeks, and finally treated with escitalopram (Esc), venlafaxine (Ven) 10 mg/kg, i.p., or combined Esc/Ven (1 mg/kg, i.p.) with zinc (5 mg/kg) for another 3 weeks. Open field (OFT), forced swim (FST), and sucrose intake (SIT) tests were used to evaluate depressive-like behavioral changes. In addition, serum, intracellular, and synaptic Zn concentrations and the level of zinc transporter (ZnT) proteins were analyzed. The OB + ZnD model induced hyperactivity in rats in the OFT, increased immobility time in the FST, and anhedonia in the SIT. Chronic treatment with Esc reduced immobility time in the FST in the OB + ZnD model. Esc/Ven +Zn increased sucrose intake in rats from the OB + ZnD group. The OB + ZnD decreased serum zinc levels and intracellular and synaptic Zn concentration in the prefrontal cortex (PFC) and cerebellum. These changes were normalized by chronic administration of Esc/Ven +Zn. Moreover, OB + ZnD decreased levels of the ZnT1 protein in the PFC and Hp and ZnT3 in Hp. Chronic administration of antidepressants did not alter the levels of ZnT proteins. The OB + ZnD model induces more depressive-like effects than either model alone. Our results show that ZnD may induce drug resistance in rats. Normalizing serum or brain zinc concentration is insufficient to reverse behavioral abnormalities caused by the OB + ZnD model. However, zinc supplementation might improve the effectiveness of antidepressants in reversing particular depression symptoms