Maternal probiotic Lactocaseibacillus rhamnosus HN001 treatment alters postpartum anxiety, cortical monoamines, and the gut microbiome.

Peripartum mood and anxiety disorders (PMADs) affect 15-20% of peripartum women and are well known to disrupt infant caregiving. A recent study in humans reported that anxiety and depressive symptoms were alleviated by peripartum treatment with the probiotic, Lactocaseibacillus rhamnosus HN001. The current study determined the effects of chronic Lactocaseibacillus rhamnosus HN001 (HN001) treatment on postpartum affective and caregiving behaviors in a laboratory rodent model. Female rats were given probiotic overnight in their drinking water, or untreated water, from the first day of pregnancy through postpartum day 10. To determine whether the HN001 effects were influenced by a background of stress, half the females underwent chronic variable pregnancy stress and the other half remained undisturbed. The results revealed that, even without pregnancy stress, HN001 reduced postpartum anxiety-related behavior, increased variability in behavioral fragmentation when dams interacted with pups, increased time away from pups, and decreased prefrontal cortex norepinephrine (NE), dopamine (DA) and serotonin (5-HT). Probiotic plus stress consistently reduced the latency to float in the forced swim test, increased DA and 5-HT turnovers in the prefrontal cortex, increased hippocampal NE, and reduced hypothalamic DA. Fecal microbe alpha and beta diversities were lower postpartum than prepartum, which was prevented by the probiotic treatment and/or stress. Across the entire sample lower postpartum anxiety behavior was associated with lower fecal Bacteroides dorei. This study reveals novel information about how L. rhamnosus HN001 influences postpartum behavior and microbiota-gut-brain physiology in female laboratory rats, with implications for probiotic supplement use by pregnant and postpartum women.

Sex Differences in Stress Response: Classical Mechanisms and Beyond.

Neuropsychiatric disorders, which are associated with stress hormone dysregulation, occur at different rates in men and women. Moreover, nowadays, preclinical and clinical evidence demonstrates that sex and gender can lead to differences in stress responses that predispose males and females to different expressions of similar pathologies. In this curated review, we focus on what is known about sex differences in classic mechanisms of stress response, such as glucocorticoid hormones and corticotrophin-releasing factor (CRF), which are components of the hypothalamicpituitary- adrenal (HPA) axis. Then, we present sex differences in neurotransmitter levels, such as serotonin, dopamine, glutamate and GABA, as well as indices of neurodegeneration, such as amyloid ß and Tau. Gonadal hormone effects, such as estrogens and testosterone, are also discussed throughout the review. We also review in detail preclinical data investigating sex differences caused by recentlyrecognized regulators of stress and disease, such as the immune system, genetic and epigenetic mechanisms, as well neurosteroids. Finally, we discuss how understanding sex differences in stress responses, as well as in pharmacology, can be leveraged into novel, more efficacious therapeutics for all. Based on the supporting evidence, it is obvious that incorporating sex as a biological variable into preclinical research is imperative for the understanding and treatment of stress-related neuropsychiatric disorders, such as depression, anxiety and Alzheimer's disease.

Practical solutions for including sex as a biological variable (SABV) in preclinical neuropsychopharmacological research.

Recently, many funding agencies have released guidelines on the importance of considering sex as a biological variable (SABV) as an experimental factor, aiming to address sex differences and avoid possible sex biases to enhance the reproducibility and translational relevance of preclinical research. In neuroscience and pharmacology, the female sex is often omitted from experimental designs, with researchers generalizing male-driven outcomes to both sexes, risking a biased or limited understanding of disease mechanisms and thus potentially ineffective therapeutics. Herein, we describe key methodological aspects that should be considered when sex is factored into in vitro and in vivo experiments and provide practical knowledge for researchers to incorporate SABV into preclinical research. Both age and sex significantly influence biological and behavioral processes due to critical changes at different timepoints of development for males and females and due to hormonal fluctuations across the rodent lifespan. We show that including both sexes does not require larger sample sizes, and even if sex is included as an independent variable in the study design, a moderate increase in sample size is sufficient. Moreover, the importance of tracking hormone levels in both sexes and the differentiation between sex differences and sex-related strategy in behaviors are explained. Finally, the lack of robust data on how biological sex influences the pharmacokinetic (PK), pharmacodynamic (PD), or toxicological effects of various preclinically administered drugs to animals due to the exclusion of female animals is discussed, and methodological strategies to enhance the rigor and translational relevance of preclinical research are proposed.

Drug-drug interactions between COVID-19 drug therapies and antidepressants.

INTRODUCTION: Antidepressants are widely used for the pharmacological treatment of anxiety and mood disorders. Since the eruption of the SARS-COV-2 pandemic and the later development of targeted treatments against COVID-19, inevitably many patients receive antidepressants as well as targeted treatments against COVID-19 against COVID-19. Co-administration of antidepressants with COVID-19 therapeutics has the potential of drug-drug interactions, of varying severity and clinical significance. AREAS COVERED: This is a curated narrative review of the current state of the art regarding drug-drug interactions between COVID-19 therapeutics and medications licensed for the pharmacotherapy of depression. A systematic search of electronic databases, using as keywords the international nonproprietaty names of currently approved COVID-19 therapeutics and antidepressants was performed, and additionally online interaction checker tools were consulted. Derived data were synthesized for each COVID-19 therapeutic and presented with up-to-date guidance. EXPERT OPINION: Several COVID-19 therapeutics have potential for drug-drug interactions with antidepressants. Remdesivir and Nirmatrelvir-Ritonavir have the higher risk, whereas several monoclonal antibodies appear safer. The most serious drug-drug interactions (serotonin syndrome and QTc prolongation) require close monitoring; however, DDI toward reducing the efficacy of antidepressants may be difficult to recognize. As COVID-19 treatment protocols take precedence, psychiatrists should exert flexibility in antidepressant use and proactively monitor treatment progress.

Τhe neuroprotective role of environmental enrichment against behavioral, morphological, neuroendocrine and molecular changes following chronic unpredictable mild stress: A systematic review.

Environmental factors interact with biological and genetic factors influencing the development and well-being of an organism. The interest in better understanding the role of environment on behavior and physiology led to the development of animal models of environmental manipulations. Environmental enrichment (EE), an environmental condition that allows cognitive and sensory stimulation as well as social interaction, improves cognitive function, reduces anxiety and depressive-like behavior and promotes neuroplasticity. In addition, it exerts protection against neurodegenerative disorders, cognitive aging and deficits aggravated by stressful experiences. Given the beneficial effects of EE on the brain and behavior, preclinical studies have focused on its protective role as an alternative, non-invasive manipulation, to help an organism to cope better with stress. A valid, reliable and effective animal model of chronic stress that enhances anxiety and depression-like behavior is the chronic unpredictable mild stress (CUMS). The variety of stressors and the unpredictability in the time and sequence of exposure to prevent habituation, render CUMS an ethologically relevant model. CUMS has been associated with dysregulation of the hypothalamic-pituitary-adrenal axis, elevation in the basal levels of stress hormones, reduction in brain volume, dendritic atrophy and alterations in markers of synaptic plasticity. Although numerous studies have underlined the compensatory role of EE against the negative effects of various chronic stress regimens (e.g. restraint and social isolation), research concerning the interaction between EE and CUMS is sparse. The purpose of the current systematic review is to present up-to-date research findings regarding the protective role of EE against the negative effects of CUMS.

Exploring a Possible Interplay between Schizophrenia, Oxytocin, and Estrogens: A Narrative Review.

Schizophrenia is characterized by symptoms of psychosis and sociocognitive deficits. Considering oxytocin's antipsychotic and prosocial properties, numerous clinical, and preclinical studies have explored the neuropeptide's therapeutic efficacy. Sex differences in the clinical course of schizophrenia, as well as in oxytocin-mediated behaviors, indicate the involvement of gonadal steroid hormones. The current narrative review aimed to explore empirical evidence on the interplay between schizophrenia psychopathology and oxytocin's therapeutic potential in consideration of female gonadal steroid interactions, with a focus on estrogens. The review was conducted using the PubMed and PsychINFO databases and conforms to the Scale for the Assessment of Narrative Review Articles (SANRA) guidelines. The results suggest a potential synergistic effect of the combined antipsychotic effect of oxytocin and neuroprotective effect of estrogen on schizophrenia. Consideration of typical menstrual cycle-related hormonal changes is warranted and further research is needed to confirm this assumption.

Sex Differences in Depression and Anxiety.

Depression and anxiety disorders carry a tremendous worldwide burden and emerge as a significant cause of disability among western societies. Both disorders are known to disproportionally affect women, as they are twice more likely to be diagnosed and moreover, they are also prone to suffer from female-specific mood disorders. Importantly, the prevalence of these affective disorders has notably risen after the COVID pandemic, especially in women. In this chapter, we describe factors that are possibly contributing to the expression of such sex differences in depression and anxiety. For this, we overview the effect of transcriptomic and genetic factors, the immune system, neuroendocrine aspects, and cognition. Furthermore, we also provide evidence of sex differences in antidepressant response and their causes. Finally, we emphasize the importance to consider sex as a biological variable in preclinical and clinical research, which may facilitate the discovery and development of new and more efficacious antidepressant and anxiolytic pharmacotherapies for both women and men.

Corticotropin releasing factor in the nucleus basalis of Meynert impairs attentional performance and reduces levels of glutamate and taurine in male and female rats.

Psychiatric disorders that are characterized by impairments in sustained attention, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), and major depression are also sensitive to exacerbation by stress. Sustained attention relies on cholinergic and non-cholinergic projections from the nucleus basalis of Meynert (NBM) in the basal forebrain to the medial prefrontal cortex (mPFC). We have previously shown that central administration of the stress neuropeptide corticotropin releasing factor (CRF) impairs performance on the sustained attention task (SAT) in adult male and female rats. The present study investigated whether this effect was mediated by CRF's action in the NBM. Rats were administered CRF in the NBM and subsequent SAT performance was measured. A high dose of CRF (100 ng) significantly impaired performance on non-signaled events across sex. Because performance on non-signaled events is believed to depend on non-cholinergic (i.e., GABA and glutamate) signaling, high performance liquid chromatography was used to quantify amino acid levels in the NBM and mPFC. We found females have higher levels of glutamate, glutamine, GABA glycine, and alanine in the NBM than males. Importantly, CRF in the NBM led to a local decrease of taurine and several amino acids involved in glutamate synthesis in males and females, changes which may mediate the CRF-induced SAT performance deficit. Together these studies suggest that CRF regulation of amino acids in the NMB contributes to stress-induced attention deficits.

Sex Differences in Blood-Brain Barrier Transport of Psychotropic Drugs.

Treatment of neuropsychiatric disorders relies on the effective delivery of therapeutic molecules to the target organ, the brain. The blood-brain barrier (BBB) hinders such delivery and proteins acting as transporters actively regulate the influx and importantly the efflux of both endo- and xeno-biotics (including medicines). Neuropsychiatric disorders are also characterized by important sex differences, and accumulating evidence supports sex differences in the pharmacokinetics and pharmacodynamics of many drugs that act on the brain. In this minireview we gather preclinical and clinical findings on how sex and sex hormones can influence the activity of those BBB transporter systems and affect the brain pharmacokinetics of psychotropic medicines. It emerges that it is not well understood which psychotropics are substrates for each of the many and not well-studied brain transporters. Indeed, most evidence originates from studies performed in peripheral tissues, such as the liver and the kidneys. None withstanding, accumulated evidence supports the existence of several sex differences in expression and activity of transport proteins, and a further modulating role of gonadal hormones. It is proposed that a closer study of sex differences in the active influx and efflux of psychotropics from the brain may provide a better understanding of sex-dependent brain pharmacokinetics and pharmacodynamics of psychotropic medicines.

Imperatorin Influences Depressive-like Behaviors: A Preclinical Study on Behavioral and Neurochemical Sex Differences.

Imperatorin, a naturally derived furanocoumarin, exerts promising neuropharmacological properties. Therefore, it might be applicable in the treatment of brain diseases such as depression. In the present project, we aimed to investigate the sex-dependent effects of imperatorin (1, 5, and 10 mg/kg) on behavior and neurochemistry associated with antidepressant effects. The depressive-like behaviors of male and female Swiss mice were investigated in a forced swim test (FST). Subsequently, High-Performance Liquid Chromatography (HPLC) was used to evaluate the level of serotonin, its metabolite, 5-HIAA, and noradrenaline, in mouse brains. The study revealed that only males responded to imperatorin (1 and 5 mg/kg) treatment and caused an antidepressant effect, such as with respect to depressive-like behaviors, lowering immobility time and increasing immobility latency. The HPLC analysis demonstrated that serotonin levels in the prefrontal cortex of females decreased with the middle dose of imperatorin (5 mg/kg), while in the male prefrontal cortex, the lower dose (1 mg/kg) boosted serotonin levels. There were no evident changes observed with respect to noradrenaline and serotonin metabolite levels in the male hippocampus. To conclude, we propose that imperatorin has antidepressant potential, seemingly only in males, influencing brain serotonin level, but the direct mechanism of action requires further investigation.

PEERS - An Open Science "Platform for the Exchange of Experimental Research Standards" in Biomedicine.

Laboratory workflows and preclinical models have become increasingly diverse and complex. Confronted with the dilemma of a multitude of information with ambiguous relevance for their specific experiments, scientists run the risk of overlooking critical factors that can influence the planning, conduct and results of studies and that should have been considered a priori. To address this problem, we developed "PEERS" (Platform for the Exchange of Experimental Research Standards), an open-access online platform that is built to aid scientists in determining which experimental factors and variables are most likely to affect the outcome of a specific test, model or assay and therefore ought to be considered during the design, execution and reporting stages. The PEERS database is categorized into in vivo and in vitro experiments and provides lists of factors derived from scientific literature that have been deemed critical for experimentation. The platform is based on a structured and transparent system for rating the strength of evidence related to each identified factor and its relevance for a specific method/model. In this context, the rating procedure will not solely be limited to the PEERS working group but will also allow for a community-based grading of evidence. We here describe a working prototype using the Open Field paradigm in rodents and present the selection of factors specific to each experimental setup and the rating system. PEERS not only offers users the possibility to search for information to facilitate experimental rigor, but also draws on the engagement of the scientific community to actively expand the information contained within the platform. Collectively, by helping scientists search for specific factors relevant to their experiments, and to share experimental knowledge in a standardized manner, PEERS will serve as a collaborative exchange and analysis tool to enhance data validity and robustness as well as the reproducibility of preclinical research. PEERS offers a vetted, independent tool by which to judge the quality of information available on a certain test or model, identifies knowledge gaps and provides guidance on the key methodological considerations that should be prioritized to ensure that preclinical research is conducted to the highest standards and best practice.

Antidepressants' effects on testosterone and estrogens: What do we know?

Various antidepressants are commonly used to treat depression and anxiety disorders, and sex differences have been identified in their efficacy and side effects. Steroids, such as estrogens and testosterone, both in the periphery and locally in the brain, are regarded as important modulators of these sex differences. This review presents published data from preclinical and clinical studies that measure testosterone and estrogen level changes during and/or after acute or chronic administration of different antidepressants. The majority of studies show an interaction between sex hormones and antidepressants on sexual function and behavior, or in depressive symptom alleviation. However, most of the studies omit to investigate antidepressants' effects on circulating levels of gonadal hormones. From data reviewed herein, it is evident that most antidepressants can influence testosterone and estrogen levels. Still, the evidence is conflicting with some studies showing an increase, others decrease or no effect. Most studies are conducted in male animals or humans, underscoring the importance of considering sex as an important variable in such investigations, especially as depression and anxiety disorders are more common in women than men. Therefore, research is needed to elucidate the extent to which antidepressants can influence both peripheral and brain levels of testosterone and estrogens, in males and females, and whether this impacts the effectiveness or side effects of antidepressants.

Detrimental effects of adolescent escalating low-dose Δ9 -tetrahydrocannabinol leads to a specific bio-behavioural profile in adult male rats.

BACKGROUND AND PURPOSE: Adolescent cannabis use is associated with adult psychopathology. When Δ9 -tetrahydrocannabinol (THC), mainly in high doses, is administered to adolescence rats there are also long lasting effects in adults. This study aims to determine the specific adult bio-behavioural profile after adolescent low-dose THC, which better mirrors adolescent recreational cannabis use. EXPERIMENTAL APPROACH: Adolescent male Sprague-Dawley rats were treated with escalating low-dose of THC. In adulthood, they were evaluated for their spontaneous locomotion, sensorimotor gating, higher order and spatial cognitive functions. Dopaminergic activity and cannabinoid receptor expression were measured in distinct brain regions. Hippocampal neurogenic activity of neural stem cells was determined and protein levels of neuroplasticity-related biomarkers were quantified. Adolescent low-dose THC exposure increased spontaneous open-field activity, without affecting prepulse inhibition and attentional set-shifting performance. Region-specific dopaminergic alterations and CB1 receptor up-regulation in the prefrontal cortex were observed. Impaired spatial memory, as assessed with the object location task and Morris water maze test, was associated with significantly decreased proliferative activity (SOX2-positive cells), neurogenic potential (decreased doublecortin-positive cells) in the adult hippocampus and defective neuroplasticity, including reduced BDNF expression in the hippocampus and prefrontal cortex. KEY RESULTS: Our findings reveal the adverse impact of adolescent low-dose THC on the psychomotor profile, dopaminergic neurotransmission, compensatory cannabinoid receptor response, cognition-related neurobiological and behavioural functions. CONCLUSION AND IMPLICATIONS: Our adolescent low-dose THC animal model does not induce tangible psychotic-like effects, such as those reported in high-dose THC studies, but it impairs cognitive functions and points to hippocampal vulnerability and disrupted neurogenesis.

Innovative screening models for the discovery of new schizophrenia drug therapies: an integrated approach.

Introduction: Schizophrenia is a severe psychiatric disorder affecting millions worldwide. However, available treatment options do not fully address the disease. Whereas current antipsychotics may control psychotic symptoms, they seem notoriously ineffective in improving negative and cognitive symptoms or in preventing functional decline. As the etiology of schizophrenia eludes us, the development of valid animal models for screening new drug targets appears to be a strenuous task.Areas covered: In this review, the authors present the key concepts that validate animal models of schizophrenia, as well as the different screening approaches for novel schizophrenia treatments. The models covered are either based on major neurotransmitter systems or neurodevelopmental, immune, and genetic approaches.Expert opinion: Sadly, due to inertia, research focuses on developing 'anti-psychotics', instead of 'anti-schizophrenia' drugs that would tackle the entire syndrome of schizophrenia. Whereas no perfect model may ever exist, combining different experimental designs may enhance validity, as the over-reliance on a single model is inappropriate. Multi-model approaches incorporating vulnerability, the 'two-hit' hypothesis, and endophenotypes offer a promise for developing new strategies for schizophrenia treatment. Forward and reverse translation between preclinical and clinical research will increase the probability of success and limit failures in drug development.

Allosteric modulation of AMPA receptors counteracts Tau-related excitotoxic synaptic signaling and memory deficits in stress- and Aß-evoked hippocampal pathology.

Despite considerable progress in the understanding of its neuropathology, Alzheimer's disease (AD) remains a complex disorder with no effective treatment that counteracts the memory deficits and the underlying synaptic malfunction triggered by the accumulation of amyloid beta (Aß) and Tau protein. Mounting evidence supports a precipitating role for chronic environmental stress and glutamatergic excitotoxicity in AD, suggesting that targeting of glutamate receptor signaling may be a promising approach against both stress and AD pathologies. In light of the limited cognitive benefit of the direct antagonism of NMDA receptors in AD, we here focus on an alternative way to modify glutamatergic signaling through positive allosteric modulation of AMPA receptors, by the use of a PAM-AMPA compound. Using non-transgenic animal model of Aß oligomer injection as well as the combined stress and Aß i.c.v. infusion, we demonstrate that positive allosteric modulation of AMPA receptors by PAM-AMPA treatment reverted memory, but not mood, deficits. Furthermore, PAM-AMPA treatment reverted stress/Aß-driven synaptic missorting of Tau and associated Fyn/GluN2B-driven excitotoxic synaptic signaling accompanied by recovery of neurotransmitter levels in the hippocampus. Our findings suggest that positive allosteric modulation of AMPA receptors restores synaptic integrity and cognitive performance in stress- and Aß-evoked hippocampal pathology. As the prevalence of AD is increasing at an alarming rate, novel therapeutic targeting of glutamatergic signaling should be further explored against the early stages of AD synaptic malfunction with the goal of attenuating further synaptic damage before it becomes irreversible.

Nucleus Reuniens Lesion and Antidepressant Treatment Prevent Hippocampal Neurostructural Alterations Induced by Chronic Mild Stress in Male Rats.

The hippocampus-prefrontal cortex circuit plays a major role in stress and in the neurobiology of depression and its treatment. Disruption of this circuit by lesioning the thalamic nucleus reuniens (RE) has been shown to prevent the detrimental effects of chronic mild stress on prefrontal cortex neuroplasticity indices in male rats. However, it remains unknown whether hippocampal neurostructural response to stress is modified by RE lesion. In the present study, adult male rats were subjected to the chronic mild stress model of depression and were treated with either vehicle or an antidepressant (i.e. sertraline). Moreover, a group of animals was subjected to RE lesion before stress exposure with or without sertraline treatment. We demonstrated that chronic mild stress induced hippocampal CA1 dendritic atrophy and this was prevented by pre-stress RE lesion to the same extent that antidepressant treatment reversed it. The present findings highlight the importance of hippocampal-prefrontal cortex communication in chronic stress effects on hippocampal neuroplasticity and contribute to the elucidation of the role of RE in neurostructural changes underlying stress-driven depression and its treatment.

[Pharmacology of ketamine and esketamine as rapid-acting antidepressants].

The lack of utter efficacy and fast action of commonly used antidepressants that selectively target the monoaminergic neurotransmission has led to the exploration of ketamine's actions. Ketamine's antidepressant effect was firstly described in 1973 and nowadays its therapeutic value as a fast- and long- lasting antidepressant has been extensively established. Ketamine is an antagonist of the N-Methyl-D-aspartate receptor (NMDAR) and its main mechanism of action via NMDAR inhibition expressed in GABAergic (gamma-Aminobutyric acid, GABA) interneurons may be relayed to its antidepressant effects. This review aims to describe the pharmacokinetic and pharmacodynamic profile of ketamine when used for treatment-resistant depression. Moreover, ketamine is a racemic mixture consisting of two enantiomers, R- and S- ketamine. We describe the pharmacology of esketamine, along with the guidelines for effective and safe intranasal administration of esketamine. Lastly, this review presents sex differences in preclinical and clinical studies of ketamine and esketamine administration.

Xanthotoxin affects depression-related behavior and neurotransmitters content in a sex-dependent manner in mice.

The present study aimed to evaluate xanthotoxin's influence on male and female Swiss mice's depression-like behaviors and investigate the potential mechanism of this effect. Naturally derived furanocoumarin (the Apiaceae family), xanthotoxin, administered acutely (12.5 mg/kg), diminished the immobility level in the forced swim test only in males. The immobility level was lower in females than males, which may be associated with a higher serotonin level in the female prefrontal cortex. A dose-dependent increase of serotonin and noradrenaline was reported in the reverse-phase ion-pair liquid chromatography in the female prefrontal cortex but not in the hippocampus. We suggest that xanthotoxin may exert antidepressant properties and affect males and females differently. The increasing level of serotonin in the male and female prefrontal cortex may underlie this effect.