Effects of pre-gestational exposure to the stressors and perinatal bupropion administration on the firing activity of serotonergic neurons and anxiety-like behavior in rats.

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.

Mirtazapine modulates Glutamate and GABA levels in the animal model of maternal depression. MRI and 1H MRS study in female rats.

We aimed to determine, using in vivo magnetic resonance, whether maternal depression induced by chronic unpredictable stress (CUS) in the pre-gestational period in female rats would be evidenced by structural or neurometabolic changes in the hippocampal region of the brain. At the same time, appropriate behavioral tests were also administered after a relatively long two-month period of a stress paradigm. The objective of the study was not only to study an animal model of CUS using magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H MRS) focused on the hippocampus, but also to use this technique to verify the effectiveness of mirtazapine antidepressant treatment. In the group with CUS, we found a significant decrease in the relative concentration of γ-aminobutyric acid (GABA/tCr) and glutamate+glutamine (Glx/tCr) compared to the control group, while we did not observe any statistically significant change in hippocampal volumes. Moreover, the forced swim test revealed an increase in depression-like behavior. The most important finding was the return of GABA/tCr and Glx/tCr levels to control levels during mirtazapine treatment; however, behavioral tests did not demonstrate any effects from mirtazapine treatment. In vivo1H MRS confirmed mirtazapine modulation of CUS in an animal model more robustly than behavioral tests.

Sex- and age- dependent effect of pre-gestational chronic stress and mirtazapine treatment on neurobehavioral development of Wistar rat offspring.

Hormonal fluctuations, such as the perinatal period, may increase susceptibility of women to depression, which in turn exert a negative impact on child's neurodevelopment, becoming a risk factor in development of neuropsychiatric disorders. Moreover, the use of antidepressants during this critical period presents a serious health concern for both the mother and the child, due to the consequences of treatment in terms of the reliability and safety for the proper neurodevelopment of the organism being not well known. Atypical antidepressants, such as mirtazapine, that targets both serotonergic and noradrenergic systems in the central nervous system (CNS), represent a novel focus of research due to its unique pharmacological profile. The aim of this work was to study the effects of maternal depression and/or perinatal antidepressant mirtazapine treatment on the neurobehavioral development of the offspring. Pre-gestationally chronically stressed or non-stressed Wistar rat dams were treated with either mirtazapine (10 mg/kg/day) or vehicle during pregnancy and lactation followed by analysis of offspring's behavior at juvenile and adolescent age. We found mirtazapine induced significant alterations of nursing behavior. In offspring, pregestational stress (PS) had an anxiogenic effect on adolescent males (p≤0.05) and increased their active behavior in forced swim test (p≤0.01). Interaction between pregestational stress and mirtazapine treatment variously induced anxiolytic changes of juvenile (p≤0.05) and adolescent (p≤0.05) females and impairment of spatial memory (p≤0.01) in adolescent females as well. Hippocampal density of synaptophysin, pre-synaptic protein marker, was decreased mainly by mirtazapine treatment. In conclusion, our results show mirtazapine induced significant alterations in maternal behavior and several sex- and age-dependent changes in neurobehavioral development of offspring caused by both prenatal mirtazapine treatment and/or chronic pregestational stress.

Maternal immune activation in rats attenuates the excitability of monoamine-secreting neurons in adult offspring in a sex-specific way.

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 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.

Electrophysiology and Behavioral Assessment of the New Molecule SMe1EC2M3 as a Representative of the Future Class of Triple Reuptake Inhibitors.

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.

Pre-gestational stress impacts excitability of hippocampal cells in vitro and is associated with neurobehavioral alterations during adulthood.

Chronic stress during pregnancy or even prior to gestation can negatively affect offspring´s neurobehavioural development. Several studies have shown, that offspring who had experienced excessive stress during gestation had higher rates of cognitive and mood disorders later during adolescence or in adulthood. Hippocampal neurons play a crucial role in the regulation of behavior, mainly in anxiety-related behaviors and spatial learning and memory. Recently, it has been shown, that excessive stress even prior to gestation could interfere with sensitive developmental processes in the brain and may affect hippocampal functioning with severe neurobehavioural consequences in later life. The aim of this work was to investigate the effects of pre-gestational stress of the rat dams on the hippocampal excitability of the pups right after the birth. Neurobehavioural consequences of pre-gestational stress were analyzed during adolescence (35-40 postnatal days) and in early adulthood (75-80 postnatal days). We have shown that even pre-gestational chronic maternal stress increased resting membrane potential, suppressed depolarization-activated action potential firing, and increased spontaneous activity of hippocampal cells from newborn offspring. Altered function of hippocampus was reflected at the behavioural level. Adolescent male offspring of dams exposed stress prior to conception showed hyperactivity-like behaviour in a new stressful environment and increased anxiety-like behaviour during adulthood compared to adult males from non-stress group. Together, this work suggests, that chronic stress even prior to gestation can interfere with functional brain development of the offspring and can cause long-term behavioural changes at the level of neurobehavioural adaptations.

Effect of Physical Exercise and Acute Escitalopram on the Excitability of Brain Monoamine Neurons: In Vivo Electrophysiological Study in Rats.

Background: The antidepressant effect of physical exercise has been reported in several clinical and animal studies. Since serotonin, norepinephrine, and dopamine play a central role in depression, it is possible that the beneficial effects of physical exercise are mediated via monoamine pathways. This study investigates the effects of voluntary wheel running on the excitability of monoamine neurons. Materials and Methods: Male Sprague-Dawley rats were used in the study. Voluntary wheel running (VWR) rats were housed in individual cages with free access to a running wheel, while control animals were housed in standard laboratory cages. After three weeks, the rats were anesthetized, and in vivo electrophysiological recordings were taken from dorsal raphe nucleus serotonin neurons, locus coeruleus norepinephrine neurons, and ventral tegmental dopamine neurons. Results: VWR stimulated activity in serotonin, but not in norepinephrine or dopamine neurons. Subsequently, acute administration of the selective serotonin reuptake inhibitor escitalopram in control rats led to complete suppression of serotonin neurons; this suppression was reversed by subsequent administration of selective antagonist of serotonin-1A receptors, WAY100135. Escitalopram induced only partial inhibition of serotonin neurons in the VWR rats while WAY100135 increased the firing activity of serotonin neurons above the baseline value. Conclusions: The beneficial effect of physical exercise on mood is mediated, at least in part, via activation of serotonin neurons. Physical exercise can potentiate the response to selective serotonin reuptake inhibitors by increasing the basal firing activity and diminishing selective serotonin reuptake inhibitor-induced inhibition of serotonin neurons.

Risks of using SSRI / SNRI antidepressants during pregnancy and lactation.

At present, affective disorders are among the most commonly diagnosed mental diseases. In pregnancy, they can occur as pre-delivery depression, recurrent depressive disorder or postnatal depression. The estimated prevalence of depressive disorders in pregnancy is approximately 9-16%, with some statistics reporting up to 20%. Approximately 2-3% of pregnant women take antidepressants during pregnancy, and the number of mothers treated increases by birth to 5-7%. Treatment of depression during pregnancy and breastfeeding is a controversial issue, as antidepressants can negatively affect the developing fetus. According to epidemiological studies, the effects of treated depression in pregnancy are related to premature birth, decreased body weight of the child, intrauterine growth retardation, neonatal adaptive syndrome, and persistent pulmonary hypertension. However, untreated depression can adversely affect maternal health and increase the risk of preeclampsia and eclampsia, as well as of subsequent postnatal depression, which can lead to disruption of the mother-child relationship. Based on the above mentioned facts, the basic question arises as to whether or not to treat depression during pregnancy and lactation.

Animal models of maternal depression for monitoring neurodevelopmental changes occurring in dams and offspring.

Depression is one of the most prevalent and life-threatening forms of mental illness affecting about 20% of the population. Depressive disorder as a biochemical phenomenon, was first recognized in the mid-20th century of research, however the etiology of this disease is still not well understood. Although the need to investigate depressive disorders has emerged from the needs of clinical practice, there are many preclinical studies, which brought new insights into this field of research. During experimental work it was crucial to develop appropriate animal models, where the neurohumoral mechanism was similar to humans. In the past decades, several animal models of maternal depression have been developed. We describe the three most popular rodent models of maternal depression which are based on 1. stress prior to gestation, 2. prenatal stress and 3. early life stress. The above-mentioned animal models appear to fulfill many criteria for a relevant animal model of depression; they alter the regulation of the HPA, induce signs of depression-like behavior and several antidepressant treatments can reverse the state induced by maternal stress. Although, they are not able to model all aspects of maternal depression, they are useful models for monitoring neurodevelopmental changes occurring in dams and offspring.

Animal tests for anxiety-like and depression-like behavior in rats.

An animal model of human behavior represents a complex of cognitive and/or emotional processess, which are translated from animals to humans. A behavioral test is developed primarily and specifically to verify and support a theory of cognition or emotion; it can also be used to verify a theory of a psychopathology, but it is not developed for a particular type of psychopathology. The paper reviews tests commonly used in novel drug discovery research. Focus is especially on tests which can evaluate anxiety-like (openfield test, novelty suppressed feeding, elevated plus maze, light/dark box, stressinduced hyperthermia) and depression-like behaviors (forced swim test, tail suspension test, sucrose preference test) as they represent an important methodological tool in pre-clinical as well as in behavioral toxicology studies.