Eliyahu Dremencov | Slovak Academy of Sciences (original) (raw)

Papers by Eliyahu Dremencov

Frontiers in Pharmacology, 2024

It is well established that monoamines, such as serotonin (5-HT), noradrenaline, and dopamine, ar... more It is well established that monoamines, such as serotonin (5-HT), noradrenaline, and dopamine, are fundamental in emotions and mood regulation. They also play a key role in the pathophysiology and treatment of mood disorders, such as unipolar and bipolar depression, as well as anxiety disorders, such as generalized anxiety, obsessive-compulsive, panic, and post-traumatic stress disorders. We may underline three factors that are of critical importance for the proper understanding of the role of monoamines in mood disorders. The first one is the autoregulatory mechanism within the monoaminergic circuits. The second one is the multiple cross-interaction between different monoamines. The third factor is the crosstalk between monoamines and other bioactive molecules influencing mood regulation and mental functions in general. Examples of particularly important bioactive molecules are amino acid neurotransmitters, trace amines (biological amines biochemically related to the “classical” monoamines, but present in the brain in trace concentrations, such as tyramine, octopamine, and tryptamine), corticosteroids, adenosine, endogenous opioids, and cannabinoids. While the auto- and cross-regulatory mechanisms of the central monoaminergic systems have been extensively studied in the last decades, the crosstalk between monoamines and specific other biomolecules involved in mood regulation received lesser attention. This Research Topic of articles was prepared in order to diminish this gap in knowledge and to stimulate future research in this direction. The task was completed thanks to the international team of researchers, coming from different parts of the world (Asia, America, Europe) and employment sectors (universities, public hospitals and research centers, and industrial enterprises). These researchers contributed their outstanding articles addressing the abovementioned points. Zhao et al. from the Qingdao University, Qingdao, China, provided a review article on endocannabinoid-monoamine interactions, learning, and memory. Lerer et al. from the Hadassah Medical Center, Jerusalem, Israel, contributed original research on the neurochemical mechanisms underlying putative beneficial effect of psychedelics in mental disorders. Dremencov et al. from the Centre of Biosciences and Jezova et al. from Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia, shared with us an original research article on functional interactions between monoamines, glutamate, and endogenous opioids, focusing on prenatal effect of the ligands of opioid receptors on monoaminergic and glutamatergic transmission. Daniels et al. from the Institute of Mental Health Research, University of Ottawa, Ottawa, Canada, prepared an original research paper on glutamate-monoamine interactions and their role in the rapid antidepressant effect of ketamine. Malik et al. from the COMSATS University Islamabad, Islamabad, Pakistan, shared with us the results of their research on the interactions between monoamines, adenosine, microelements and steroids, with a practical focus on the putative anxiolytic and antidepressant-like effects of a natural element, diosgenin. Kolaczynska et al. from the University of Basel, Basel, Switzerland, and their co-authors from the Medical University of Vienna, Vienna, Austria (Dino Luethi), ReseaChem GmbH, Burgdorf, Switzerland (Daniel Trachsel), and Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Basel, Switzerland (Marius C. Hoener), shared with us their interesting and actual results on psychedelics and “classical” monoamines-trace amines interactions. The original findings published in the current Research Topic of articles clearly reflect the broadening of the field of classical monoamines towards a complex cocktail of interactive actions of neurotransmitters and other biologically active substances. Of particular importance are the relationships of monoamines with glutamate, endogenous cannabinoids and opioids, adenosine, microelements, glucocorticoids, and trace amines. There is a clear motivation for future research in this important field of neuroscience related to the development, course, and treatment of mental disorders.

General physiology and biophysics, 2024

The arcuate nucleus (ARN) of the hypothalamus is involved in multiple biological functions, such ... more The arcuate nucleus (ARN) of the hypothalamus is involved in multiple biological functions, such as feeding, sexual activity, and the regulation of the cardiovascular system. It was reported that leptin increased c-Fos expression in the proopiomelanocortin (POMC)-and decreased it in the neuropeptide-Y (NPY)-positive neurons of the ARN, suggesting that it stimulates the former, and inhibits the later. This study aimed at the direct electrophysiological examination of the effect of leptin on ARN neurons and to investigate potential sex-dimorphic changes. Wistar rats were anesthetized with urethane and the electrodes were inserted into the ARN. After a spontaneous active neuron was recorded for at least one minute, leptin was administered intravenously, and the firing activity of the same neuron was recorded for two additional minutes. It was found that approximately half of the ARN neurons had an excitatory, and another half an inhibitory response to the leptin administration. The excitability of the neurons with excitatory response to leptin was not different between the sexes. The average firing rate of the neurons with inhibitory response to leptin in females was, however, significantly lower comparing to the males. The obtained results demonstrate that the ARN neurons with stimulatory response to leptin are POMC and those with inhibitory response are NPY neurons. NPY Y1 receptor be might responsible, at least in part, for the sex differences in the excitability of the neurons putatively identified as NPY neurons.

Frontiers in Pharmacology, 2024

Background: There is growing evidence that the treatment of several mental disorders can potentia... more Background: There is growing evidence that the treatment of several mental disorders can potentially benefit from activation of delta-opioid receptors. In the future, delta-agonists with a safe pharmacological profile can be used for the treatment of mood disorders in pregnant women. However, the data on prenatal exposure to delta-opioid agonists are missing. The present study is aimed to test the hypothesis that the activation of delta-opioid receptors during gravidity has positive effects on the behaviour accompanied by changes in glutamate and monoamine neurotransmission. Methods: Gestating Wistar rats were chronically treated with a selective deltaagonist SNC80 or vehicle. Adult male and female offspring underwent novel object recognition (for the assessment of cognition) and open field (for the assessment of anxiety and habituation) tests, followed by in vivo electrophysiological examination of the activity of hippocampal glutamate and midbrain serotonin (5-HT) and dopamine neurons. Results: We found that the maternal treatment with SNC80 did not affect the offspring's anxiety, habituation, and 5-HT neuronal firing activity. Female offspring of SNC80-treated dams exhibited improved novelty recognition associated with decreased firing rate and burst activity of glutamate and dopamine neurons. Conclusion: Maternal treatment with delta-opioid agonists during gestation may have a pro-cognitive effect on offspring without any negative effects on anxiety and habituation. The putative pro-cognitive effect might be mediated via mechanism(s) involving the firing activity of hippocampal glutamate and mesolimbic dopamine neurons.

Behavioural brain research, 2023

Exposure by women to stressors before pregnancy increases their risk of contracting prenatal depr... more Exposure by women to stressors before pregnancy increases their risk of contracting prenatal depression, a condition which typically may require antidepressant treatment. And even though such perinatal antidepressant treatment is generally considered to be safe. For the mother, its effects on the development and functioning of the offspring`s brain remain unknown. In this study, we aimed to investigate the effects of pregestational chronic unpredictable stress (CUS) and perinatal bupropion on the anxiety behavior and firing activity of the dorsal raphe nucleus (DRN) serotonin (5-HT) neurons. Female rats underwent CUS for three weeks before mating. Bupropion was administered to them from gestation day ten until their offspring were weaned. Behavioral (elevated plus maze or EPM test) and neurophysiological (single-unit in vivo electrophysiology) assessments were performed on offspring who reached the age of 48-56 days. We found that maternal CUS and perinatal bupropion, as separate factors on their own, did not change offspring behavior. There was, however, an interaction between their effects on the number of entries to the open arms and time spent in the intersection: maternal CUS tended to decrease these values, and perinatal bupropion tended to diminish CUS effect. Maternal CUS increased the firing activity of 5-HT neurons in males, but not females. Perinatal bupropion did not alter the firing activity of 5-HT neurons but tended to potentiate the maternal CUS-induced increase in 5-HT neuronal firing activity. The CUS-induced increase in firing activity of 5-HT neurons might be a compensatory mechanism that diminishes the negative effects of maternal stress. Perinatal bupropion does not alter the offspring`s anxiety and firing activity of 5-HT, but it does intervene in the effects of maternal stress.

Drug and Alcohol Dependence, 2023

Fibroblast growth factor 2 (FGF2) is involved in the development and maintenance of the brain dop... more Fibroblast growth factor 2 (FGF2) is involved in the development and maintenance of the brain dopamine system. We previously showed that alcohol exposure alters the expression of FGF2 and its receptor, FGF receptor 1 (FGFR1) in mesolimbic and nigrostriatal brain regions, and that FGF2 is a positive regulator of alcohol drinking. Here, we determined the effects of FGF2 and of FGFR1 inhibition on alcohol consumption, seeking and relapse, using a rat operant self-administration paradigm. In addition, we characterized the effects of FGF2-FGFR1 activation and inhibition on mesolimbic and nigrostriatal dopamine neuron activation using in vivo electrophysiology. We found that recombinant FGF2 (rFGF2) increased the firing rate and burst firing activity of dopaminergic neurons in the mesolimbic and nigrostriatal systems and led to increased operant alcohol selfadministration. In contrast, the FGFR1 inhibitor PD173074 suppressed the firing rate of these dopaminergic neurons, and reduced operant alcohol self-administration. Alcohol seeking behavior was not affected by PD173074, but this FGFR1 inhibitor reduced post-abstinence relapse to alcohol consumption, albeit only in male rats. The latter was paralleled by the increased potency and efficacy of PD173074 in inhibiting dopamine neuron firing. Together, our findings suggest that targeting the FGF2-FGFR1 pathway can reduce alcohol consumption, possibly via altering mesolimbic and nigrostriatal neuronal activity.

General Physiology and Biophysics, 2023

It was previously reported that the delta opioid receptor (DOR) agonist SNC80 and antagonist nalt... more It was previously reported that the delta opioid receptor (DOR) agonist SNC80 and antagonist naltrindole modulate the excitability of hippocampal glutamate neurons in primary cultures. The present study aimed to investigate the acute effects of these ligands on the firing activity of hippocampal cornu ammonis 1/3 (CA1/3) glutamate, dorsal raphe nucleus (DRN) serotonin (5-HT), locus coeruleus (LC) noradrenaline, and ventral tegmental area (VTA) dopamine neurons in in vivo conditions. Adult Wistar male rats were used. SNC80 and naltrindole were administered intravenously. Neuronal firing activity was assessed using extracellular single-unit electrophysiology. SNC80, administered first at 1-3 mg/kg, dose-dependently inhibited CA1/3 glutamate, DRN 5-HT, and VTA dopamine neurons. Naltrindole, administered at 1-3 mg/kg after SNC80, did not have any additional effect. Naltrindole, administered first at 1-3 mg/kg, stimulated DRN 5-HT neurons in a dose-dependent manner; this stimulation was dose-dependently reversed by 1-3 mg/kg of SNC80. SNC80 and naltrindole inhibited LC noradrenaline neurons when only they were co-administered at 3 mg/kg, and only when SNC80 was administered first. In conclusion, DOR ligands alter the firing activity of hippocampal glutamate and brainstem monoamine neurons in in vivo conditions. The psychoactive effects of DOR ligands, reported in previous studies, might be explained, at least in part, by their ability to modulate the firing activity of hippocampal glutamate and brainstem monoamine neurons.

Pharmacological Reports, 2023

Background Short-term treatment with non-peptide agonists of delta-opioid receptors, such as agon... more Background Short-term treatment with non-peptide agonists of delta-opioid receptors, such as agonist SNC80, induced behavioral effects in rodents, which could be modulated via changes in central neurotransmission. The present experiments aimed at testing the hypothesis that chronic treatment with SNC80 induces anxiolytic effects associated with changes in hippocampal glutamate and brainstem monoamine pathways. Methods Adult male Wistar rats were used in experiments. Rats were treated with SNC80 (3 mg/kg/day) for fourteen days. Neuronal excitability was assessed using extracellular in vivo single-unit electrophysiology. The behavioral parameters were examined using the elevated plus maze and open field tests. Results Chronic SNC80 treatment increased the excitability of hippocampal glutamate and ventral tegmental area dopamine neurons and had no effect on the firing activity of dorsal raphe nucleus serotonin cells. Chronic SNC80 treatment induced anxiolytic effects, which were, however, confounded by increased locomotor activity clearly confirmed in an open field test. The ability to cope with stressful situations and habituation processes in a novel environment was not influenced by chronic treatment with SNC80. Conclusion Our study suggests that the psychoactive effects of SNC80 might be explained by its ability to stimulate hippocampal glutamate and mesolimbic dopamine transmission.

Drug Discovery Today, 2023

Perinatal depression is the most common psychiatric complication of pregnancy, with its detriment... more Perinatal depression is the most common psychiatric complication of pregnancy, with its detrimental effects on maternal and infant health commonly underrated. There is a pressing need for specific molecular biomarkers, with pregnancy-related decline in brain-derived neurotrophic factor (BDNF) in the blood and downregulation of TrkB receptor in the brain reported in both clinical and preclinical studies. In this review, we highlight the emerging role of BDNF in reproductive biology and discuss evidence suggesting its deficiency as a risk factor for perinatal depression. With the increasing evidence for restoration of serum BDNF levels by antidepressant therapy, the strengthening association of perinatal depression with deficiency of BDNF advocates its potential as a surrogate endpoint for preclinical and clinical studies.

Molecular Psychiatry, 2022

Trace amine-associated receptor 1 (TAAR1) has been recently identified as a target for the future... more Trace amine-associated receptor 1 (TAAR1) has been recently identified as a target for the future antidepressant, antipsychotic, and anti-addiction drugs. Full (e.g. RO5256390) and partial (e.g. RO5263397) TAAR1 agonists showed antidepressant-, antipsychotic-and anti-addiction-like behavioral effects in rodents and primates. Acute RO5256390 suppressed, and RO5263397 stimulated serotonin (5-HT) neurons of the dorsal raphe nucleus (DRN) and dopamine neurons of the ventral tegmental area (VTA) in brain slices, suggesting that the behavioral effects of TAAR1 ligands involve 5-HT and dopamine. For more comprehensive testing of this hypothesis, we examined acute and chronic effects of RO5256390 and RO5263397 on monoamine neurons in in vivo conditions. Excitability of 5-HT neurons of the DRN, noradrenaline neurons of the locus coeruleus (LC), and dopamine neurons of the VTA was assessed using single-unit electrophysiology in anesthetized rats. For acute experiments, RO5256390 and RO5263397 were administered intravenously; neuronal excitability after RO5256390 and RO5263397 administration was compared to the basal activity of the same neuron. For chronic experiments, RO5256390 was administered orally for fourteen days prior to electrophysiological assessments. The neuronal excitability in RO5256390-treated rats was compared to vehicle-treated controls. We found that acute RO5256390 inhibited 5-HT and dopamine neurons. This effect of RO5256390 was reversed by the subsequent and prevented by the earlier administration of RO5263397. Acute RO5256390 and RO5263397 did not alter the excitability of LC noradrenaline neurons in a statistically significant way. Chronic RO5256390 increased excitability of 5-HT neurons of the DRN and dopamine neurons of the VTA. In conclusion, the putative antidepressant and antipsychotic effects of TAAR1 ligands might be mediated, at least in part, via the modulation of excitability of central 5-HT and dopamine neurons.

General physiology and biophysics, 2019

The aim of this study was to investigate the effect of chronic predator scent stress (PSS) on mon... more The aim of this study was to investigate the effect of chronic predator scent stress (PSS) on monoamine levels in rat thalamus and hypothalamus. Rats were exposed to the PSS (sand containing cat urine) for ten minutes daily for ten days. Control animals were exposed to the sand containing clean water. Fifteen days later, rats' behavior and thalamic and hypothalamic levels of monoamines were analyzed. PSS rats had elevated anxiety, increased thalamic serotonin and decreased hypothalamic dopamine concentrations. This decrease in hypothalamic dopamine may explain, at least in part, lowered corticosterone levels observed in PSS animals in our previous studies.

Pharmacological Reports, 2022

Background: Exposure to predator scent (PS) has been used as a model of stress associated with da... more Background: Exposure to predator scent (PS) has been used as a model of stress associated with danger to life and body integrity. Under stress conditions, the brain serotoninergic (5-HT) system plays an important role. Methods: We tested the hypothesis that repeated PS exposure alters the excitability of 5-HT neurons of the dorsal raphe nucleus. To study the mechanisms involved, we approached serum and adrenal corticosterone and aldosterone concentrations, as well as brain-derived neurotrophic factor (BDNF) expression. Adult male Sprague-Dawley rats were exposed to PS for ten minutes daily for ten consecutive days. Two weeks after the last exposure, electrophysiological and biochemical assessments were performed. Results: Measurements by in vivo electrophysiology showed increased firing activity of 5-HT neurons in rats exposed to PS. Exposure to PS resulted in reduced serum corticosterone and aldosterone concentrations. Concentrations of both corticosteroids in the adrenal glands and the relative weight of the adrenals were unaffected. The gene expression of hippocampal BDNF of rats exposed to PS remained unaltered. PS exposure failed to induce changes in the gene expression of selected adrenal steroidogenic factors. Conclusion: Reduced corticosteroid concentrations in the blood appear to be the result of increased metabolism and/or tissue uptake rather than altered steroidogenesis. The decrease in circulating corticosterone in rats who experienced repeated PS may represent part of the mechanisms leading to increased excitability of 5-HT neurons. The increase in 5-HT neuronal activity might be an important compensatory mechanism designated to diminish the harmful effects of the repeated PS exposure on the brain.

General Physiology and Biophysics, 2022

The concentrations of circulating glucocorticoids are regulated by their synthesis and metabolism... more The concentrations of circulating glucocorticoids are regulated by their synthesis and metabolism. Cytochrome P450 (CYP), primarily expressed in the liver, is one of the main metabolizers of glucocorticoids. Since glucocorticoids, as well as monoamines, are fundamental in stress, the link between hepatic glucocorticoid metabolism and central monoamine transmission might be important in pathophysiology of stress-related disorders. We had previously reported that CYP inhibition by proadifen (SKF525) led to the inhibition of central serotonin (5-HT) neurons. The aim of this study was to investigate the effect of SKF525 on the excitability of central catecholamine neurons. Adult male Wistar rats were administered SKF525 forty-eight, twenty-four, and one hour before electrophysiological assessments. Control animals were injected saline. Rats were anesthetized with chloral hydrate and glass electrodes were inserted into the locus coeruleus (LC) or ventral tegmental area (VTA). Noradrenaline neurons of the LC and dopamine of the VTA neurons were identified, and their firing activity was recorded. It was found that the SKF525 enhanced the excitability of noradrenaline and reduced the excitability of dopamine neurons. We suggest that corticosterone-induced inhibition of 5-HT neurons underlines, at least in part, the ability of SKF525 to stimulate noradrenaline neurons. The inhibitory effect of SKF525 on dopamine neurons might be in turn secondary to the stimulatory effect of this compound on noradrenaline neurons.

International journal of molecular sciences, 2021

Depression associated with poor general medical condition, such as post-stroke (PSD) or post-myoc... more 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-HT1A receptors are compatible with selective 5-HT serotonin reuptake inhibitors (SSRIs) and antagonists of 5-HT3 and 5-HT1A 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-HT1A antagonist WAY100135. We suggest that L-17 is a potent 5-HT reuptake inhibitor and partial antagonist of 5-HT3 and 5-HT1A 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.

Neuroscience Letters, 2021

Notwithstanding major advances in psychotherapeutics, their efficacy and specificity remain limit... more Notwithstanding major advances in psychotherapeutics, their efficacy and specificity remain limited. The slow onset of beneficial outcomes and numerous adverse effects of widely used medications remain of chief concern, warranting in-depth studies. The majority of frontline therapies are thought to enhance the endogenous monoaminergic drive, to initiate a cascade of events leading to lasting functional and structural plasticity. The latter also involves alterations in trophic factor signalling, including brain-derived neurotrophic factor (BDNF), NGF (nerve growth factors), vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), glial cell-derived neurotrophic factor (GDNF), and others. In several major mental disorders, emerging data suggest protective and restorative effects of trophic factors in preclinical models, when applied on their own. Antidepressant outcomes of VGF and FGF2, for instance, were shown in experimental animals, while BDNF and GDNF prove useful in the treatment of addiction, schizophrenia, and autism spectrum disorders. The main challenge with the effective translation of these and other findings in the clinic is the knowledge gap in action mechanisms with potential risks, as well as the lack of effective platforms for validation under clinical settings. Herein, we review the state-of-the-art and advances in the therapeutic use of trophic factors in several major neuropsychiatric disorders.

Stress, 2020

There is evidence that plasma cortisol concentration can be either increased or decreased in pati... more There is evidence that plasma cortisol concentration can be either increased or decreased in patients with depression and related anxiety and stress-related disorders; the exact pathophysiological mechanisms of this state are not almost clear. Several distinct theories were proposed and mechanisms, which could lead to decreased glucocorticoid signaling and/or levels, were described. However, there is a possible drawback in almost all the theories proposed: insufficient attention to the inflammatory process, which is undoubtedly present in several stress-related disorders, including post-traumatic stress disorder (PTSD). Previous studies only briefly mentioned the presence of an inflammatory reaction's signs in PTSD, without giving it due importance, although recognizing that it can affect the course of the disease. With that, the state of biochemical changes, characterized by the low glucocorticoids, glucocorticoid receptor's resistance and the signs of the persistent inflammation (with the high levels of circulating cytokines) might be observed not only in PTSD but in coronary heart diseases and sys-temic chronic inflammatory diseases (rheumatoid arthritis) as well. That is why the present review aims to depict the pathophysiological mechanisms, which lead to a decrease in glucocorticoids in PTSD due to the action of inflammatory stimuli. We described changes in the glucocorticoid system and inflam-matory reaction as parts of an integral system, where glucocorticoids and the glucocorticoid receptor reside at the apex of a regulatory network that blocks several inflammatory pathways, while decreased glucocorticoid signaling and/or level leads to unchecked inflammatory reactions to promote patholo-gies such as PTSD. LAY SUMMARY This review emphasizes the importance of inflammatory reaction in the development of puzzling conditions sometimes observed in severe diseases including post-traumatic stress disorder-the decreased levels of glucocorticoids in the blood. Following the classical concepts, one would expect an increase in glucocorticoid hormones, since they are part of the feedback mechanism in the immune system, which reduces stress and inflammation. However, low levels of glucocorticoid hormones are also observed. Thus, this review describes potential mechanisms, which can lead to the development of such a state.

European Neuropsychopharmacology, 2021

KEYWORDS Lipopolysaccharide (LPS); Prenatal immune activation; Serotonin (5-HT); Noradrenaline; D... more KEYWORDS Lipopolysaccharide (LPS); Prenatal immune activation; Serotonin (5-HT); Noradrenaline; Dopamine; Electrophysiology in vivo. Abstract Higher risk of depression and schizophrenia in descendants of mothers experienced acute infection during the pregnancy has been reported. Since monoamines are fundamental in mentioned psychopathologies, it is possible that maternal immune activation leads to impaired functioning of serotonin (5-HT), noradrenaline, and dopamine neurons in offspring. To test this hypothesis, we examined the effect of maternal immune activation by lipopolysaccharide (LPS) in rats on the excitability of monoamine-secreting neurons in the offspring. LPS was administered during days 15-19 of the gestation in the rising doses of 20-80 μg/kg; control dams received vehicle. During days 53-63 postpartum , rats were anesthetized and electrodes were inserted into the dorsal raphe nucleus, locus coeruleus, and ventral tegmental area for in vivo excitability assessment of 5-HT, noradrenaline, and dopamine neurons. Maternal immune activation suppressed the firing rate of 5-HT neurons in both sexes and stimulated the firing rate of dopamine neurons in males. Decrease in the firing rate of 5-HT neurons was accompanied with an increase, and Please cite this article as: K. Csatlosova, E. Bogi and B. Durisova et al., Maternal immune activation in rats attenuates the excitability of monoamine-secreting neurons in adult offspring in a sex-specific way, European Neuropsychopharmacology, https://doi. JID: NEUPSY [m6+; December 16, 2020;21:18 ] increase in the firing rate of dopamine neurons with a decrease, in the density of spontaneously active cells. Maternal immune activation also decreased the variability of interspike intervals in 5-HT and dopamine neurons. It is possible that the alteration of excitability of 5-HT and dopamine neurons by maternal immune activation is involved in the psychopathologies induced by infectious disease during the pregnancy. Stimulation of dopamine excitability in males might be a compensatory mechanism secondary to the maternal immune challenge-induced suppression of 5-HT neurons.

International Journal of Molecular Sciences, 2020

Atypical antipsychotic drugs were introduced in the early 1990s. Unlike typical antipsychotics, w... more Atypical antipsychotic drugs were introduced in the early 1990s. Unlike typical antipsychotics, which are effective only against positive symptoms of schizophrenia, atypical antipsychotics are effective against negative and cognitive symptoms as well. Furthermore, they are effective not only in psychotic but also in affective disorders, on their own or as adjuncts to antidepressant drugs. This review presents the neural mechanisms of currently existing atypical antipsychotics and putative antipsychotics currently being investigated in preclinical and clinical studies and how these relate to their effectiveness in mood disorders such as depression, anxiety, and post-traumatic stress disorder (PTSD). Typical antipsychotics act almost exclusively on the dopamine system. Atypical drugs, however, modulate serotonin (5-HT), norepinephrine, and/or histamine neurotransmission as well. This multimodal mechanism of action putatively underlies the beneficial effect of atypical antipsychotics in mood and anxiety disorders. Interestingly, novel experimental drugs having dual antipsychotic and antidepressant therapeutic potential, such as histamine, adenosine, and trace amine-associated receptors (TAAR) ligand, are also characterized by a multimodal stimulatory effect on central 5-HT, norepinephrine, and/or histamine transmission. The multimodal stimulatory effect on central monoamine neurotransmission may be thus primarily responsible for the combined antidepressant and antipsychotic therapeutic potential of certain central nervous system (CNS) drugs.

Pharmacological Reports, 2020

Background: Delta-opioid receptor (DOR)-mediated modulation of hippocampal neural networks is inv... more Background: Delta-opioid receptor (DOR)-mediated modulation of hippocampal neural networks is involved in emotions, cognition, and in pathophysiology and treatment of mood disorders. In this study, we examined the effects of DOR agonist (SNC80) and antagonist (naltrindole) on the excitability of individual hippocampal neurons.
Methods: Primary neuronal cultures were prepared from hippocampi of newborn rats and cultivated in vitro for 8-14 days (DIV8-14). The effects of SNC80 naltrindole on evoked and spontaneous action potentials (APs) were measured at DIV8-9 and DIV13-14, respectively.
Results: SNC80 (100 µM) potentiated spontaneous AP firing and stimulated sodium current; naltrindole had opposite effects. The stimulatory effect of 100 µM of SNC80 was revoked by pre-administration of 1 µM of naltrindole. SNC80 and naltrindole induced similar inhibitory effects on the evoked AP firing and on the calcium current. Further, SNC80 inhibited both peak and sustained potassium currents. Naltrindole had no effect on potassium currents.
Conclusion: We suggest that the effects of naltrindole and high concentration of SNC80 on the sodium currents are mediated via DORs and underlying the changes in spontaneous activity. The inhibitory effects of SNC80 on calcium and potassium currents might also be DOR-dependent; these currents might mediate SNC80 effect on the evoked AP firing. The inhibitory effects of naltrindole on calcium and of low doses of SNC80 on sodium currents might be however DOR-independent. The behavioral effects of SNC80 and naltrindole, observed in previous studies, might be mediated, at least in part, via the modulatory effect of these ligands on the excitability of hippocampal neurons.

Psychoneuroendocrinology, 2020

Background: Repeated exposure to predator scent stress (PSS) has been used as an animal model of ... more Background: Repeated exposure to predator scent stress (PSS) has been used as an animal model of complex post-traumatic stress disorder (CPTSD). The aim of the current study was to assess brain monoamines and their primary metabolites concentrations in male Wistar rats (16 control, 19 exposed to chronic PSS). Methods: Rats were exposed to PSS for ten days. Fourteen days later, the rats' anxiety index (AI) was assessed with an elevated plus maze test; based on differences in AI, the rats were segregated into low-(AI ≤ 0.8, n = 9) and high-(AI > 0.8, n = 10) anxiety phenotypes. Plasma corticosterone levels were measured by radio-immunoassay. Brain monoamines and their metabolites were measured using high-performance liquid chromatography with electrochemical detector. Results: PSS exposure led to a significant increase in average rats' AI and a reduction in plasma corticosterone levels. Medullar catecholamines and hippocampal and neocortical norepinephrine levels were increased, and pontine norepinephrine and cerebellar dopamine decreased in PSS-exposed rats. Cerebellar norepinephrine levels were increased, and midbrain, hippocampal, and neocortical 5-HT and hypothalamic and hippocampal dopamine levels-decreased in high-, but not in low-anxiety rats. The decrease in hippocampal dopamine levels was accompanied by an increase of DOPAC levels, suggesting and abnormal metabolism of this transmitter. Conclusion: Reductions in 5-HT and dopamine in mid-and forebrain brain areas are associated with stress susceptibility in rodents and perhaps also with PTSD vulnerability in humans. Dopamine and 5-HT metabolism and its modulation by glucocorticoids appear to play a role in stress susceptibility and in CPTSD.

Molecules, 2019

SMe1EC2M3 is a pyridoindole derivative related to the neuroleptic drug carbidine. Based on the st... more SMe1EC2M3 is a pyridoindole derivative related to the neuroleptic drug carbidine. Based on the structural similarities of SMe1EC2M3 and known serotonin (5-HT), norepinephrine, and dopamine reuptake inhibitors, we hypothesized that this compound may also have triple reuptake inhibition efficacy and an antidepressant-like effect. PreADMET and Dragon software was used for in silico prediction of pharmacokinetics and pharmacodynamics of SMe1EC2M3. Forced swim test was used to evaluate its antidepressant-like effects. Extracellular in vivo electrophysiology was used to assess 5-HT, norepinephrine, and dopamine reuptake inhibition efficacy of SMe1EC2M3. PreADMET predicted reasonable intestinal absorption, plasma protein binding, and blood-brain permeability for SMe1EC2M3. Dragon forecasted its efficiency as an antidepressant. Using behavioral measurements, it was found that SMe1EC2M3 decreased immobility time and increase swimming time during the forced swim test (FST). Electrophysiological investigations showed that SMe1EC2M3 dose-dependently suppressed the excitability of 5-HT neurons of the dorsal raphe nucleus (DRN), norepinephrine neurons of the locus coeruleus (LC), and dopamine neurons of the ventral tegmental area (VTA). The SMe1EC2M3-induced suppression of 5-HT, norepinephrine, and dopamine neurons was reversed by the antagonists of serotonin-1A (5-HT1A; WAY100135), α-2 adrenergic (α2, yohimbine), and dopamine-2 receptors (D2, haloperidol), respectively. We conclude that SMe1EC2M3 is prospective triple 5-HT, norepinephrine, and dopamine reuptake inhibitor with antidepressant-like properties, however future studies should be performed to complete the pharmacological profiling of this compound.

Frontiers in Pharmacology, 2024

General physiology and biophysics, 2024

Frontiers in Pharmacology, 2024

Behavioural brain research, 2023

Drug and Alcohol Dependence, 2023

General Physiology and Biophysics, 2023

Pharmacological Reports, 2023

Drug Discovery Today, 2023

Molecular Psychiatry, 2022

General physiology and biophysics, 2019

Pharmacological Reports, 2022

General Physiology and Biophysics, 2022

International journal of molecular sciences, 2021

Neuroscience Letters, 2021

Stress, 2020

European Neuropsychopharmacology, 2021

International Journal of Molecular Sciences, 2020

Pharmacological Reports, 2020

Psychoneuroendocrinology, 2020

Molecules, 2019

This monograph is a collection of selected articles on the subject of mood disorders such as depr... more This monograph is a collection of selected articles on the subject of mood disorders such as depression and schizophrenia. It is divided into 3 sections: 1) Research methods in psychopharmacology - which highlights some established experimental techniques to study mood disorders in human and relevant animal models, 2) Pathophysiology of mood disorders – which explains the physiological and pharmacological mechanisms responsible for mood disorders and 3) New strategies for the treatment of mood disorders – a concluding section that provides recent examples on the beneficial effects of pharmacological and non-pharmacological interventions in the relief of mood disorders. The e-book serves as a primer for graduate students and researchers interested in the physiology and treatment of affective psychological disorders. Free sample is available for downloading; order the whole book at: http://benthamscience.com/ebooks/9781608054671/index.htm

All existing antidepressant drugs are characterized by relatively long delay (two-eight weeks) be... more All existing antidepressant drugs are characterized by relatively long delay (two-eight weeks) between the beginning of the medication and onset of therapeutic effect of the treatment. One of the goals of psycho-pharmacological research is to create novel treatment strategies with rapid onset of the beneficial effect. The research project described in this book aimed to assess, using an animal model of depression,dynamical changes in brain neuro-chemistry and behavior following the administration of different antidepressant drugs. The main intend was to understand the neuronal mechanism of early onset of behavioral effects of antidepressant treatment. The research was focused on reward system and on serotonin-dopamine interactions in the nucleus accumbens. This book dedicated to the memory of author's devoted teacher and his primary scientific mentor, Dr. Michael E. Newman.

This chapter aims to summarize the up-today evidence-based biomedical knowledge on serotonin-2A (... more This chapter aims to summarize the up-today evidence-based biomedical knowledge on serotonin-2A (5-HT 2A) receptors and their role in pathophysiology and treatment of central nervous system (CNS) disorders, with a primary focus on depression. The first paragraph provides a brief introduction to serotonin (5-HT) system and 5-HT receptors, focusing on serotonin-2 (5-HT2) family and 5-HT2A receptor specifically. The second paragraph is focused on molecular genetics of 5-HT2A receptors, polymorphism of 5-HT2A receptor (5HT2AR) gene, 5HT2AR gene epigenetic mechanisms, such as DNA methylation, and post-translational modifications of 5-HT2AR messenger ribonucleic acid (mRNA), such as alternative splicing. The molecular and cellular pharmacology and physiology of 5-HT2A receptors in normal and pathological conditions are discussed in the third paragraph. The 5-HT2A receptors-acting ligands are addresses. The fourth paragraph describes the role of 5-HT receptors in the interaction between 5-HT and other neurotransmitter systems in health and in CNS disorders. The fifth and the final paragraph specifically deals with the role of 5-HT2A receptor in pathophysiology and treatment of depression, focusing on the 5-HT2A receptor expressed in the hippocampus.

Neurobiology of Mood Disorders, Feb 2014

There are number of lines of evidence that the neurotransmitter norepinephrine (NE) might be very... more There are number of lines of evidence that the neurotransmitter norepinephrine (NE) might be very important in pathophysiology of anxiety and mood disorders. Firstly, NE projections innervate the limbic system, suggesting the involvement of NE in the regulation of emotions and cognition. Secondly, NE interacts with serotonin (5-HT) and dopamine (DA) systems, which also play very important roles in the regulation of mood. Thirdly, it has been shown that various agents for increasing NE availability, such as NE reuptake inhibitors, are also effective antidepressant drugs. And fourthly, the depletion of NE can result in the relapse of depression after successful treatment with antidepressant drugs. All these pieces of evidence suggest that the stimulation of NE transmission can be beneficial in the treatment of affective disorders. However, different psychiatric medications have distant effects on NE transmission. The current chapter analyses the effect of psychiatric medications on NE system and proposes how the treatment outcome might be improved.

Pathophysiology of Central 5-HT2C Receptors, Jul 2011

Next Generation Antidepressant, May 2010

Prevalence of depression has increased progressively over the last decades. Besides the impact on... more Prevalence of depression has increased progressively over the last decades. Besides the impact on human quality of life, the pharmaco-economical impact of this syndrome requires ongoing development of newer, more powerful antidepressants. While optimizing existing therapeutic compounds, multiple approaches can be taken to generate superiority over these compounds. The delay in onset of action of antidepressants is of relevance as the presence of side effects during the initial absence of clinical effects causes low therapy compliance. Obviously, a decrease in onset of action would overcome this problem. Current therapy still induces considerable side-effects depending on the class of antidepressants used. Reducing these has multiple advantages, such as it will increase compliance but also facilitate the rapid and safe initiation of drug treatment. In line with safety requirements is the notion that new antidepressants should not be prone to hazardous effects in overdose, nor should they induce dangerous interactions by interfering with other treatment. Finally, it is currently recognized that depression is a cluster of symptoms rather than a concise disease. To this end, it is recognized that more tailored treatments might be required in the future. Arguably targeting sub symptoms and co-morbid features like anxiety are of high relevance. Attempts to improve antidepressants have been made into monoamine related strategies, but also more recently in non monoamine strategies. The effectiveness of monoamine targeted selective, dual- and triple uptake inhibitors and augmented uptake inhibitors is discussed. In addition, new strategies like monoamine non-uptake inhibitor drugs or non monoamine drugs exerting effects on Glu, GABA, Substance P, and acetylcholine are discussed, as are more miscellaneous approaches.

In vivo identification and characterization of the spontaneously active neurons in the arcuate nucleus of hypothalamus in male and female Sprague-Dawley rats

Introduction: The current study aimed to identify and characterize the spontaneous firing activit... more Introduction: The current study aimed to identify and characterize the spontaneous firing activity of the neurons of rat arcuate nucleus (ARN) of the hypothalamus in vivo. The ARN contains two types of neurons: pro-opiomelanocortin (POMC) neurons which release β-endorphin and neuropeptide-Y (NPY) secreting neurons [1]. These neurons play an important role in pain modulation, reward, motivation, and appetite regulation. Therefore, in vivo electrophysiological characterization of the firing activity of ARN neurons might contribute to better understanding of their function under physiological and pathophysiological conditions.

Methods: Adult male and female Sprague-Dawley rats (200–250 g) were used in experiments. Rats were anesthetized with urethane (1.25 g/kg, i.p.) and mounted in stereotaxic apparatus (David Kopf, Tujunga, CA, USA). One-mm scull holes were drilled above the ARN (3.9 mm posterior and 0.6 mm lateral from the bregma). The glass electrodes filled with 2M NaCl (impedance 4–6 MΩ) were lowered throughout the lateral ARN three times in each animal (3.8, 3.9, and 4.0 mm posterior and 0.6 mm lateral from the bregma) to the depth from 9.5 to 10.0 mm ventral from the brain surface [2]. Spontaneously active neurons were recorded using HEKA-10 amplifier.

Results: Spontaneously active neurons were detected in the lateral ARN of both male and female rats. The firing pattern of the spontaneously active ARN neurons included both single action potentials and short bursts of two or three action potentials. The average duration of an action potential was ∼5 msec, with ∼1.5 msec depolarization, ∼1 msec repolarization, and ∼3 msec refractory period. The average number of spontaneously active neurons per electrode tack was slightly higher in males (2.65±0.33) than in females (1.85±0.25); however, this difference was not statistically significant. The average firing rate of spontaneous active ARN neurons was 3.14±0.50 in males (59 neurons from 7 rats) and 3.02±0.95 in females (23 neurons from 6 rats). According to preliminary results, in male rats, 75% of neurons were stimulated by intravenous administration of 1 mg/kg of leptin and 25% neurons did not respond to the leptin administration. In female rats, 50% of neurons were activated, and 25% of neurons were inhibited by leptin and 25% of neurons did not respond to the leptin administration. In summary, a significant main effect of time (Fdf17,143 = 2.45, p < 0.01) and significant interaction between gender and time (Fdf17,143 = 1.75, p < 0.05) in the response of spontaneous active ARN neurons to leptin administration was observed (two-way ANOVA for repeated measures).

Conclusion: Based on previous study [1], it can be suggested that ARN neurons which were stimulated by leptin are POMC cells. The cells which were inhibited by leptin are likely to be NPY neurons. It is possible that male Sprague-Dawley rats have higher density of spontaneously active POMC and smaller density of spontaneous active NPY neurons.

References

[1] Elias, C.F., Aschkenasi, C., Lee, C., Kelly, J., Ahima, R.S., Bjorbaek, C., Flier, J.S., Saper, C.B., Elmquist, J.K., 1999. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron 23, 775–86.

[2] Paxinos, G., Watson, C., 2013. The Rat Brain in Stereotaxic Coordinates, Seventh Edition. Academic Press, Cambridge, UK.

Disclosure statement: This work was supported by Slovak Academy of Sciences Scholarship and by VEGA grant 2/0024/15. Leptin was provided by the National Hormone & Peptide Program (NHPP) of the University of California in Los Angeles, CA, USA.