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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 13647

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Dr. Eliyahu Dremencov

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Guest Editor

Institute of Molecular Physiology and Genetics, Centre for Biosciences, Slovak Academy of Sciences, Dúbravská cesta 9, 840 05 Bratislava, Slovak Republic
Interests: interaction between monoamines and other neuromodulatroy systems (e.g., adrenocortical steroids and endogeneous purines and opioids) in pathophysilogy and treatment of depression and related CNS disorders

Special Issue Information

Dear Colleagues,

The proposed Special Issue will be dedicated to current strategies for the development of new central nervous system (CNS) medications, with a primary focus on antidepressant drugs. Depression is a severe chronic disorder of the CNS, affecting up to 20% of the world population; it is considered by the World Health Organization as the second major reason for disability worldwide. Depression is commonly comorbid with other stress-related mood disorders, such as anxiety, panic, and post-traumatic stress disorder (PTSD). These brain illnesses have similar etiology and pathophysiology. Despite the relative progress in the pharmaceutical treatment of depression and related disorders, the clinical efficacy of the contemporary antidepressant and mood stabilizing drugs remains limited. Different strategies have been proposed for the optimization of treatment of depression and related CNS disorders, such as combinations of existing antidepressant and mood-stabilizing drugs, combinations of pharmaceutical and non-pharmaceutical treatment interventions, development of multimodal drugs acting on several monoamine systems of the brain, as well as searching for new CNS targets other than monoamines (e.g., adrenocortical steroids and endogenous purines and opioids).

Dr. Eliyahu Dremencov
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Keywords

Stress-related CNS disorders
Pharmaceutical and non-pharmaceutical treatment strategies
Monoamines
Adrenocortical steroids

Published Papers (6 papers)

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Research

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14 pages, 2202 KiB

Open AccessArticle

Effect of Haloperidol and Olanzapine on Hippocampal Cells’ Proliferation in Animal Model of Schizophrenia

by Jana Osacka, Alexander Kiss, Zuzana Bacova and Andrej Tillinger

Int. J. Mol. Sci. 2022, 23(14), 7711; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23147711 - 12 Jul 2022

Cited by 5 | Viewed by 1570

Abstract

Aberrant neurogenesis in the subventricular zone (SVZ) and hippocampus (HIP) contributes to schizophrenia pathogenesis. Haloperidol (HAL) and olanzapine (OLA), commonly prescribed antipsychotics for schizophrenia treatment, affect neurogenesis too. The effect of HAL and OLA on an mHippoE-2 cell line was studied in vitro where we measured the cell number and projection length. In vivo, we studied the gene expression of DCX, Sox2, BDNF, and NeuN in the SVZ and HIP in an MK-801-induced animal schizophrenia model. Cells were incubated with HAL, OLA, and MK-801 for 24, 48, and 72 h. Animals were injected for 6 days with saline or MK801 (0.5 mg/kg), and from the 7th day with either vehicle HAL (1 mg/kg) or OLA (2 mg/kg), for the next 7 days. In vitro, HAL and OLA dose/time-dependently suppressed cells’ proliferation and shortened their projection length. HAL/OLA co-treatment with MK-801 for 24 h reversed HAL’s/OLA’s inhibitory effect. In vivo, HAL and OLA suppressed DCX and NeuN genes’ expression in the HIP and SVZ. MK-801 decreased DCX and NeuN genes’ expression in the HIP and OLA prevented this effect. The data suggest that subchronic HAL/OLA treatment can inhibit DCX and NeuN expression. In an MK-801 schizophrenia model, OLA reversed the MK-801 inhibitory effect on DCX and NeuN and HAL reversed the effect on DCX expression; however, only in the HIP. Full article

(This article belongs to the Special Issue Psychoneuropharmacology)

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12 pages, 2840 KiB

Open AccessArticle

Combined In Silico, Ex Vivo, and In Vivo Assessment of L-17, a Thiadiazine Derivative with Putative Neuro- and Cardioprotective and Antidepressant Effects

by Alexey Sarapultsev, Pavel Vassiliev, Daniil Grinchii, Alexander Kiss, Mojmir Mach, Jana Osacka, Alexandra Balloova, Ruslan Paliokha, Andrey Kochetkov, Larisa Sidorova, Petr Sarapultsev, Oleg Chupakhin, Maxim Rantsev, Alexander Spasov and Eliyahu Dremencov

Int. J. Mol. Sci. 2021, 22(24), 13626; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413626 - 20 Dec 2021

Cited by 1 | Viewed by 1949

Abstract

Depression associated with poor general medical condition, such as post-stroke (PSD) or post-myocardial infarction (PMID) depression, is characterized by resistance to classical antidepressants. Special treatment strategies should thus be developed for these conditions. Our study aims to investigate the mechanism of action of 2-morpholino-5-phenyl-6H-1,3,4-thiadiazine, hydrobromide (L-17), a recently designed thiadiazine derivative with putative neuro- and cardioprotective and antidepressant-like effects, using combined in silico (for prediction of the molecular binding mechanisms), ex vivo (for assessment of the neural excitability using c-Fos immunocytochemistry), and in vivo (for direct examination of the neuronal excitability) methodological approaches. We found that the predicted binding affinities of L-17 to serotonin (5-HT) transporter (SERT) and 5-HT₃ and 5-HT_1A receptors are compatible with selective 5-HT serotonin reuptake inhibitors (SSRIs) and antagonists of 5-HT₃ and 5-HT_1A receptors, respectively. L-17 robustly increased c-Fos immunoreactivity in the amygdala and decreased it in the hippocampus. L-17 dose-dependently inhibited 5-HT neurons of the dorsal raphe nucleus; this inhibition was partially reversed by the 5-HT_1A antagonist WAY100135. We suggest that L-17 is a potent 5-HT reuptake inhibitor and partial antagonist of 5-HT₃ and 5-HT_1A receptors; the effects of L-17 on amygdaloid and hippocampal excitability might be mediated via 5-HT, and putatively mediate the antidepressant-like effects of this drug. Since L-17 also possesses neuro- and cardioprotective properties, it can be beneficial in PSD and PMID. Combined in silico predictions with ex vivo neurochemical and in vivo electrophysiological assessments might be a useful strategy for early assessment of the efficacy and neural mechanism of action of novel CNS drugs. Full article

(This article belongs to the Special Issue Psychoneuropharmacology)

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15 pages, 2195 KiB

Open AccessArticle

Modulation of PARP-1 Activity in a Broad Time Window Attenuates Memorizing Fear

by Einat Elharrar, Yahav Dikshtein, Sapir Meninger-Mordechay, Yehuda Lichtenstein and Gal Yadid

Int. J. Mol. Sci. 2021, 22(12), 6170; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126170 - 08 Jun 2021

Cited by 3 | Viewed by 1762

Abstract

The amygdala plays a critical role in the acquisition and consolidation of fear-related memories. Recent studies have demonstrated that ADP-ribosylation of histones, accelerated by PARPs, affects the chromatin structure and the binding of chromatin remodeling complexes with transcription factors. Inhibition of PARP-1 activity during the labile phase of re-consolidation may erase memory. Accordingly, we investigated the possibility of interfering with fear conditioning by PARP-1 inhibition. Herein, we demonstrate that injection of PARP-1 inhibitors, specifically into the CeA or i.p., in different time windows post-retrieval, attenuates freezing behavior. Moreover, the association of memory with pharmacokinetic timing of PARP inhibitor arrival to the brain enabled/achieved attenuation of a specific cue-associated memory of fear but did not hinder other memories (even traumatic events) associated with other cues. Our results suggest using PARP-1 inhibitors as a new avenue for future treatment of PTSD by disrupting specific traumatic memories in a broad time window, even long after the traumatic event. The safety of using these PARP inhibitors, that is, not interfering with other natural memories, is an added value. Full article

(This article belongs to the Special Issue Psychoneuropharmacology)

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17 pages, 1371 KiB

Open AccessArticle

Learned Immobility Produces Enduring Impairment of the HPA Axis Reactivity in Mice without Replicating the Broad Spectrum of Depressive-Like Phenotype

by Sébastien Bullich, Sarah Delcourte, Nasser Haddjeri and Bruno P. Guiard

Int. J. Mol. Sci. 2021, 22(2), 937; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22020937 - 19 Jan 2021

Cited by 2 | Viewed by 1923

Abstract

The forced swim stress test (FST) is widely used for screening pharmacological or non-pharmacological strategies with potential antidepressant activities. Recent data have suggested that repeated FST for five consecutive days (i.e., 5d-RFSS) could be used to generate a robust depressive-like phenotype in mice. However, the face, construct, and predictive validities of 5d-RFSS have been recently challenged. This study took advantage of recent findings showing that mice vulnerability to anxiety is enhanced when animals are stressed during the dark phase, to provide new insight into the relevance of this model. Our results showed a progressive increase in time of immobility in 5d-RFSS mice relative to control non-stressed animals (sham). Three weeks later, we noticed that 5d-RFSS mice injected with the vehicle compound (Veh) still exhibited a high level of immobility in the FST whereas this behavior was reversed by the antidepressant drug amitriptyline (AMI). However, 5d-RFSS/Veh and 5d-RFSS mice/AMI mice showed normal performances in the open field, the novelty suppressed feeding and the tail suspension tests. Despite this lack of generalized behavioral deficits, an impairment of different parameters characterizing the hypothalamic-pituitary-adrenal (HPA) axis reactivity was evidenced in 5d-RFSS mice/Veh but not in 5d-RFSS mice/AMI. Despite anomalies in the HPA axis, the activity of the central serotonergic system remained unaffected in 5d-RFSS mice relative to controls. From our results, it is suggested that learned immobility does not replicate the broad spectrum of depressive symptoms observed in other chronic models of depression such as the unpredictable chronic mild stress (UCMS) model, the chronic social defeat stress (CSDS) model or chronic corticosterone (CORT) exposure but its influence on the HPA axis is remarkable. Further experiments are warranted to makes this model suitable for modelling depression and therefore refine its translational applicability. Full article

(This article belongs to the Special Issue Psychoneuropharmacology)

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16 pages, 3038 KiB

Open AccessArticle

First Evidence of Kv3.1b Potassium Channel Subtype Expression during Neuronal Serotonergic 1C11 Cell Line Development

by Hager Tabka, Amani Cheikh, Sonia Maatoug, Mohamed El Ayeb, Saïd Bendahhou and Rym Benkhalifa

Int. J. Mol. Sci. 2020, 21(19), 7175; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197175 - 29 Sep 2020

Cited by 3 | Viewed by 2535

Abstract

Kv3.1 channel is abundantly expressed in neurons and its dysfunction causes sleep loss, neurodegenerative diseases and depression. Fluoxetine, a serotonin selective reuptake inhibitor commonly used to treat depression, acts also on Kv3.1. To define the relationship between Kv3.1 and serotonin receptors (SR) pharmacological modulation, we showed that 1C11, a serotonergic cell line, expresses different voltage gated potassium (VGK) channels subtypes in the presence (differentiated cells (1C11D)) or absence (not differentiated cells (1C11ND)) of induction. Only Kv1.2 and Kv3.1 transcripts increase even if the level of Kv3.1b transcripts is highest in 1C11D and, after fluoxetine, in 1C11ND but decreases in 1C11D. The Kv3.1 channel protein is expressed in 1C11ND and 1C11D but is enhanced by fluoxetine only in 1C11D. Whole cell measurements confirm that 1C11 cells express (VGK) currents, increasing sequentially as a function of cell development. Moreover, SR 5HT1b is highly expressed in 1C11D but fluoxetine increases the level of transcript in 1C11ND and significantly decreases it in 1C11D. Serotonin dosage shows that fluoxetine at 10 nM blocks serotonin reuptake in 1C11ND but slows down its release when cells are differentiated through a decrease of 5HT1b receptors density. We provide the first experimental evidence that 1C11 expresses Kv3.1b, which confirms its major role during differentiation. Cells respond to the fluoxetine effect by upregulating Kv3.1b expression. On the other hand, the possible relationship between the fluoxetine effect on the kinetics of 5HT1b differentiation and Kv3.1bexpression, would suggest the Kv3.1b channel as a target of an antidepressant drug as well as it was suggested for 5HT1b. Full article

(This article belongs to the Special Issue Psychoneuropharmacology)

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Review

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20 pages, 621 KiB

Open AccessReview

Targeting the Reconsolidation of Licit Drug Memories to Prevent Relapse: Focus on Alcohol and Nicotine

by Segev Barak and Koral Goltseker

Int. J. Mol. Sci. 2021, 22(8), 4090; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22084090 - 15 Apr 2021

Cited by 8 | Viewed by 2897

Abstract

Alcohol and nicotine are widely abused legal substances worldwide. Relapse to alcohol or tobacco seeking and consumption after abstinence is a major clinical challenge, and is often evoked by cue-induced craving. Therefore, disruption of the memory for the cue–drug association is expected to suppress relapse. Memories have been postulated to become labile shortly after their retrieval, during a “memory reconsolidation” process. Interference with the reconsolidation of drug-associated memories has been suggested as a possible strategy to reduce or even prevent cue-induced craving and relapse. Here, we surveyed the growing body of studies in animal models and in humans assessing the effectiveness of pharmacological or behavioral manipulations in reducing relapse by interfering with the reconsolidation of alcohol and nicotine/tobacco memories. Our review points to the potential of targeting the reconsolidation of these memories as a strategy to suppress relapse to alcohol drinking and tobacco smoking. However, we discuss several critical limitations and boundary conditions, which should be considered to improve the consistency and replicability in the field, and for development of an efficient reconsolidation-based relapse-prevention therapy. Full article

(This article belongs to the Special Issue Psychoneuropharmacology)

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