Pharmacokinetic/pharmacodynamic modeling of cortical dopamine concentrations after quetiapine lipid core nanocapsules administration to schizophrenia phenotyped rats.

Schizophrenia (SCZ) response to pharmacological treatment is highly variable. Quetiapine (QTP) administered as QTP lipid core nanocapsules (QLNC) has been shown to modulate drug delivery to the brain of SCZ phenotyped rats (SPR). In the present study, we describe the brain concentration-effect relationship after administrations of QTP as a solution or QLNC to SPR and naïve animals. A semimechanistic pharmacokinetic (PK) model describing free QTP concentrations in the brain was linked to a pharmacodynamic (PD) model to correlate the drug kinetics to changes in dopamine (DA) medial prefrontal cortex extracellular concentrations determined by intracerebral microdialysis. Different structural models were investigated to fit DA concentrations after QTP dosing, and the final model describes the synthesis, release, and elimination of DA using a pool compartment. The results show that nanoparticles increase QTP brain concentrations and DA peak after drug dosing to SPR. To the best of our knowledge, this is the first study that combines microdialysis and PK/PD modeling in a neurodevelopmental model of SCZ to investigate how a nanocarrier can modulate drug PK and PD, contributing to the development of new treatment strategies for SCZ.

Environmental enrichment affects behavioral and pharmacological response to antidepressants in CF1 mice.

It has been described that environmental enrichment (EE) exerts beneficial effects on cognitive and emotional performances, dendritic branching, synaptic density, neurogenesis and modulation of neurotrophic systems and neurotransmitters in rodents. However, the influence of EE on pharmacological and behavioral responses in animal models of psychiatric disorders has not been fully established. In this context, the aim of this study was to evaluate the influence of exposure to EE on mice behavior in the open field test (OFT) and forced swimming tests (FST), as well as the response to antidepressant drugs (fluoxetine 30 mg/kg and bupropion 30 mg/kg, p.o.). CF1 mice were exposed to an enriched housing condition at different developmental stages: from mating to postnatal day (PND) 55 (lifelong enrichment), from mating to PND21 (perinatal enrichment) and from PND21 to PND55 (post-weaning enrichment). At PND58 the male offspring were evaluated in the OFT and FST. BDNF gene expression in the hippocampus was determined through qPCR. Mice exposed to perinatal enrichment remained longer in the peripheral zone of the OFT and performed fewer grooming than mice housed under standard condition, and these effects were independent of drug treatment. Post-weaning and lifelong enrichment increased grooming behavior. Bupropion reduced grooming in all groups except in perinatal enriched. In turn, fluoxetine decreased grooming only in post-weaning enriched group. None of the enriched housing conditions altered the immobility time in the FST, which indicates that EE had no antidepressant-like effect. However, all enriched housing conditions abolished the anti-immobility effect of bupropion. None of the EE protocols affected BDNF hippocampal expression. The main conclusion is that mice behavior in the OFT is sensitive to alterations in the housing environment and depends on the developmental stage of exposure. Bupropion and fluoxetine yielded divergent responses depending on the housing condition, which suggests that EE modulates monoaminergic neurotransmission pathways.

Effects of Taurine in Mice and Zebrafish Behavioral Assays With Translational Relevance to Schizophrenia.

BACKGROUND: Altered redox state and developmental abnormalities in glutamatergic and GABAergic transmission during development are linked to the behavioral changes associated with schizophrenia. As an amino acid that exerts antioxidant and inhibitory actions in the brain, taurine is a potential candidate to modulate biological targets relevant to this disorder. Here, we investigated in mice and zebrafish assays whether taurine prevents the behavioral changes induced by acute administration of MK-801 (dizocilpine), a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist. METHODS: C57BL/6 mice were i.p. administered with saline or taurine (50, 100, and 200 mg/kg) followed by MK-801 (0.15 mg/kg). Locomotor activity, social interaction, and prepulse inhibition of the acoustic startle reflex were then assessed in different sets of animals. Zebrafish were exposed to tank water or taurine (42, 150, and 400 mg/L) followed by MK-801 (5 µM); social preference and locomotor activity were evaluated in the same test. RESULTS: MK-801 induced hyperlocomotion and disrupted sensorimotor gating in mice; in zebrafish, it reduced sociability and increased locomotion. Taurine was mostly devoid of effects and did not counteract NMDA antagonism in mice or zebrafish. DISCUSSION: Contradicting previous clinical and preclinical data, taurine did not show antipsychotic-like effects in the present study. However, it still warrants consideration as a preventive intervention in animal models relevant to the prodromal phase of schizophrenia; further studies are thus necessary to evaluate whether and how taurine might benefit patients.

What do male and female zebrafish prefer? Directional and colour preference in maze tasks.

Studies regarding the animals' innate preferences help elucidate and avoid probable sources of bias and serve as a reference to improve and develop new behavioural tasks. In zebrafish research, data obtained in behavioural assessments are often not replicated between research groups or even inside the same laboratory raising huge concerns about replicability and reproducibility. Among the potential causes that are not well considered, sexual differences can be a probable source of bias. Thus, this study aimed to investigate the male and female zebrafish directional and colour preferences in the plus-maze and T-maze behavioural tasks. Experiment 1 evaluated directional preference, and experiment 2 evaluated colour preference in a plus-maze task; experiment 3 evaluated preference between black or white in a T-maze task. Individual preferences were expressed as the percentage of time spent in each zone. Our results showed that male and female zebrafish demonstrated no difference in directional preference in the plus-maze task. Surprisingly, male and female zebrafish showed colour preference differences in the plus-maze task; males did not show any colour preference, while female zebrafish demonstrated a red preference compared to white, blue and yellow colours. Moreover, both male and female zebrafish demonstrated a strong black colour preference compared to the white colour in the T-maze task. Our findings characterized the spontaneous preference of male and female zebrafish for direction and colour, identifying possible biases and providing insights that contribute to the standardization of future protocols.

Behavioral manifestations in rodent models of autism spectrum disorder: protocol for a systematic review and network meta-analysis.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental condition associated with severe social communication, interaction, and sensory processing impairments. Efforts to understand its etiology and pathophysiology are crucial for improving treatment and prevention measures. Preclinical models of ASD are essential for investigating the biological mechanisms and should present translatability potential. We aim to evaluate the consistency of the most commonly used rodent models of ASD in displaying autistic-like behavior through a systematic review and meta-analysis. METHODS: This review will focus on the most frequently used autism models, surveying studies of six genetic (Ube3a, Pten, Nlgn3, Shank3, Mecp2, and Fmr1), three chemically induced (valproic acid (VPA), lipopolysaccharide (LPS), and polyinosinic:polycytidylic acid (poly(I:C))), and one inbred model (BTBR T+ Itpr3tf/J mouse strain). Two independent reviewers will screen the records. Data extraction of behavioral outcomes and risk of bias evaluation will be performed. We will conduct a meta-analysis whenever at least five studies investigate the same model and behavioral outcome. We will also explore the heterogeneity and publication bias. Network meta-analyses are planned to compare different models. DISCUSSION: By shortening the gap between animal behavior and human endophenotypes or specific clinical symptoms, we expect to help researchers on which rodent models are adequate for research of specific behavioral manifestations of autism, which potentially require a combination of them depending on the research interest. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021226299 .

Glutamate NMDA Receptor Antagonists with Relevance to Schizophrenia: A Review of Zebrafish Behavioral Studies.

Schizophrenia pathophysiology is associated with hypofunction of glutamate NMDA receptors (NMDAR) in GABAergic interneurons and dopaminergic hyperactivation in subcortical brain areas. The administration of NMDAR antagonists is used as an animal model that replicates behavioral phenotypes relevant to the positive, negative, and cognitive symptoms of schizophrenia. Such models overwhelmingly rely on rodents, which may lead to species-specific biases and poor translatability. Zebrafish, however, is increasingly used as a model organism to study evolutionarily conserved aspects of behavior. We thus aimed to review and integrate the major findings reported in the zebrafish literature regarding the behavioral effects of NMDAR antagonists with relevance to schizophrenia. We identified 44 research articles that met our inclusion criteria from 590 studies retrieved from MEDLINE (PubMed) and Web of Science databases. Dizocilpine (MK-801) and ketamine were employed in 29 and 10 studies, respectively. The use of other NMDAR antagonists, such as phencyclidine (PCP), APV, memantine, and tiletamine, was described in 6 studies. Frequently reported findings are the social interaction and memory deficits induced by MK-801 and circling behavior induced by ketamine. However, mixed results were described for several locomotor and exploratory parameters in the novel tank and open tank tests. The present review integrates the most relevant results while discussing variation in experimental design and methodological procedures. We conclude that zebrafish is a suitable model organism to study drug-induced behavioral phenotypes relevant to schizophrenia. However, more studies are necessary to further characterize the major differences in behavior as compared to mammals.

How do zebrafish (Danio rerio) respond to MK-801 and amphetamine? Relevance for assessing schizophrenia-related endophenotypes in alternative model organisms.

Schizophrenia pathophysiology has been associated with dopaminergic hyperactivity, NMDA receptor hypofunction, and redox dysregulation. Most behavioral assays and animal models to study this condition were developed in rodents, leaving room for species-specific biases that could be avoided by cross-species approaches. As MK-801 and amphetamine are largely used in mice and rats to mimic schizophrenia features, this study aimed to compare the effects of these drugs in several zebrafish (Danio rerio) behavioral assays. Male and female adult zebrafish were exposed to MK-801 (1, 5, and 10 µM) or amphetamine (0.625, 2.5, and 10 mg/L) and observed in paradigms of locomotor activity and social behavior. Oxidative parameters were quantified in brain tissue. Our results demonstrate that MK-801 disrupted social interaction, an effect that resembles the negative symptoms of schizophrenia. It also altered locomotion in a context-dependent manner, with hyperactivity when fish were tested in the presence of social cues and hypoactivity when tested alone. On the other hand, exposure to amphetamine was devoid of effects on locomotion and social behavior, while it increased lipid peroxidation in the brain. Key outcomes induced by MK-801 in rodents, such as social interaction deficit and locomotor alterations, were replicated in zebrafish, corroborating previous studies and reinforcing the use of zebrafish to study schizophrenia-related endophenotypes. More studies are necessary to assess the predictive validity of preclinical paradigms with this species and ultimately optimize the screening of potential novel treatments.

Anti-stress effects of the glucagon-like peptide-1 receptor agonist liraglutide in zebrafish.

Stress-related disorders are extremely harmful and cause significant impacts on the individual and society. Despite the limited evidence regarding glucagon-like peptide-1 receptor (GLP-1R) and mental disorders, a few clinical and preclinical studies suggest that modulating this system could improve symptoms of stress-related disorders. This study aimed to investigate the effects of liraglutide, a GLP-1R agonist, on neurobehavioral phenotypes and brain oxidative status in adult zebrafish. Acute liraglutide promoted anxiolytic-like effects in the light/dark test, while chronic treatment blocked the impact of unpredictable chronic stress on behavioral and physiological parameters. Taken together, our study demonstrates that liraglutide is active on the zebrafish brain and may counteract some of the effects induced by stress. More studies are warranted to further elucidate the potential of GLP-1R agonists for the management of brain disorders.

Swimming in the maze: An overview of maze apparatuses and protocols to assess zebrafish behavior.

Most preclinical behavioral assays use rodents as model animals, leaving room for species-specific biases that could be avoided by an expanded cross-species approach. In this context, zebrafish emerges as an alternative model organism to study neurobiological mechanisms of anxiety, preference, learning, and memory, as well as other phenotypes with relevance to neuropsychiatric disorders. In recent years, several zebrafish studies using different types of mazes have been published. However, the protocols and apparatuses' shapes and dimensions vary widely in the literature. This variation may puzzle researchers attempting to implement maze behavioral assays and challenges the reproducibility across institutions. This review aims to provide an overview of the behavioral paradigms assessed in different types of mazes in zebrafish reported in the last couple of decades. Also, this review aims to contribute to a better characterization of multi-behavioral assessment in zebrafish.

Quantification of neurotransmitters in microdialysate samples following quetiapine dosing to schizophrenia phenotyped rats using a validated LC-MS/MS method.

A versatile method was developed and validated for simultaneous determination of the monoamine neurotransmitters (MNT) dopamine (DA), 3-4-dyhydroxyphenilacetic acid (DOPAC), homovanilic acid (HVA), serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA) in rat brain microdialysate samples using high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS). The method allowed for small sample volume, using positive and negative ionization mode in a single run analysis without any derivatization or cleanup steps. Analytes were quantified at concentrations ranging from 100 ng/mL to 0.05, 10, 0.5, 0.1 or 1 ng/mL (lower limit of quantification, LLOQ) of DA, DOPAC, HVA, 5-HT and 5-HIAA, respectively, showing linearity (r > 0.98), accuracy, and precision (R.S.D ± 15%) according to validation limits accepted by international guidelines. The method was successfully applied for monitoring the concentration changes of MNT in microdialysate samples from medium prefrontal cortex of Wistar rats in a neurodevelopmental model of schizophrenia before and after quetiapine 5 mg/kg i.v. bolus dose administration. No alterations in MNTs were observed in schizophrenia phenotyped rats (SPR) in comparison to the baseline shading a light on the limited response rate to antipsychotic drugs observed in chronic schizophrenic patients.

Semi-Mechanistic Pharmacokinetic Modeling of Lipid Core Nanocapsules: Understanding Quetiapine Plasma and Brain Disposition in a Neurodevelopmental Animal Model of Schizophrenia.

This study investigated plasma and brain disposition of quetiapine lipid core nanocapsules (QLNC) in naive and schizophrenic (SCZ-like) rats and developed a semimechanistic model to describe changes in both compartments following administration of the drug in solution (FQ) or nanoencapsulated. QLNC (1 mg/ml) presented 166 ± 39 nm, low polydispersity, and high encapsulation (93.0% ± 1.4%). A model was built using experimental data from total and unbound plasma and unbound brain concentrations obtained by microdialysis after administration of single intravenous bolus dose of FQ or QLNC to naive and SCZ-like rats. A two-compartment model was identifiable both in blood and in brain with a bidirectional drug transport across the blood-brain barrier (CLin and CLout). SCZ-like rats' significant decrease in brain exposure with FQ (decrease in CLin) was reverted by QLNC, showing that nanocarriers govern quetiapine tissue distribution. Model simulations allowed exploring the potential of LNC for brain delivery. SIGNIFICANCE STATEMENT: A population approach was used to simultaneously model total and unbound plasma and unbound brain quetiapine concentrations allowing for quantification of the rate and extent of the drug's brain distribution following administration of both free drug in solution or as nanoformulation to naive and SCZ-like rats. The model-based approach is useful to better understand the possibilities and limitations of this nanoformulation for drug delivering to the brain, opening the opportunity to use this approach to improve SCZ-treatment-limited response rates.

Quetiapine lipid core nanocapsules restore prepulse inhibition deficits in a neurodevelopmental model of schizophrenia in male and female rats.

Lipid core nanocapsules (LNC) have been extensively studied as a new treatment strategy to improve therapeutic effects of antipsychotic drugs. We investigated the efficacy of quetiapine LNCs (QLNCs) on the poly(i:c) model of schizophrenia in both male and female rats using the pre-pulse inhibition of startle response (PPI) test paradigm after evaluating the outcomes of three different poly(i:c) doses administered to pregnant damns at GD15 on neurodevelopmental outcomes of maternal immune activation (MIA) in adult offspring. QTP solution was not capable of producing a reversal in the sensorimotor gating-disruptive effect caused by the prenatal poly(i:c) exposure. The same dose of QTP given as QLNCs significantly improved PPI-impairment. This is the first study reporting the restoration of the PPI deficits in a neurodevelopmental model of SCZ using LNCs. This is a promising delivery system strategy to improve antipsychotic effects contributing to the development of better SCZ pharmacological treatments.

Withdrawal effects following repeated ethanol exposure are prevented by N-acetylcysteine in zebrafish.

Alcohol abuse is a highly prevalent condition that substantially contributes to global morbidity and mortality. Most available pharmacological treatments offer little efficacy as relapse rates are high, due in part to the symptoms experienced during abstinence. The roles of oxidative stress and glutamatergic transmission in alcohol withdrawal have been demonstrated in several studies, suggesting that restoration of oxidative status and glutamatergic function may represent a new pharmacological target to prevent the behavioral and biochemical alterations observed during withdrawal. A well-known antioxidant and glutamatergic modulator, N-acetylcysteine (NAC), has shown promise in treating a variety of psychiatric conditions, including substance use disorders, and is a promising molecule in the management of alcohol withdrawal syndrome. Thus, the aim of this study was to investigate whether NAC is able to prevent the expression of behavioral and biochemical alterations induced by ethanol withdrawal in chronically exposed zebrafish. Animals were exposed to ethanol (1% v/v, 20 min) or control water, followed by treatment with NAC (1 mg/L, 10 min) or control water daily for 8 days; 24 h later, experimental animals were submitted to the novel tank test (NTT). Ethanol withdrawal decreased the distance traveled and increased the number of immobile episodes, indicating locomotor deficits; moreover, withdrawal decreased the number of entries and time spent in the top area, while increasing time spent in the bottom area, indicating anxiety-like behavior. Alcohol withdrawal also increased lipid peroxidation (TBARS) and decreased non-protein reduced sulfhydryl (NPSH) and superoxide dismutase (SOD) and catalase (CAT) activities. NAC attenuated these locomotor deficits and prevented the manifestation of anxiety-like behavior as well as the oxidative damage observed following ethanol withdrawal. Given its favorable safety profile, additional clinical and preclinical studies are warranted to unravel the long-term effects of NAC in the context of alcohol abuse and the exact mechanisms involved. Nevertheless, our study adds to the existing body of evidence supporting the clinical evaluation of NAC in substance abuse disorders.

Inhaled linalool-induced sedation in mice.

Linalool is a monoterpene often found as a major component of essential oils obtained from aromatic plant species, many of which are used in traditional medical systems as hypno-sedatives. Psychopharmacological evaluations of linalool (i.p. and i.c.v.) revealed marked sedative and anticonvulsant central effects in various mouse models. Considering this profile and alleged effects of inhaled lavender essential oil, the purpose of this study was to examine the sedative effects of inhaled linalool in mice. Mice were placed in an inhalation chamber during 60 min, in an atmosphere saturated with 1% or 3% linalool. Immediately after inhalation, animals were evaluated regarding locomotion, barbiturate-induced sleeping time, body temperature and motor coordination (rota-rod test). The 1% and 3% linalool increased (p<0.01) pentobarbital sleeping time and reduced (p<0.01) body temperature. The 3% linalool decreased (p<0.01) locomotion. Motor coordination was not affected. Hence, linalool inhaled for 1h seems to induce sedation without significant impairment in motor abilities, a side effect shared by most psycholeptic drugs.

MK801- and scopolamine-induced amnesias are reversed by an Amazonian herbal locally used as a "brain tonic".

RATIONALE: Traditional remedies prepared from Ptychopetalum olacoides (PO) are used throughout the Amazon to alleviate age-related conditions. These formulas are mainly used by elders, and alleged effects may be related to the anticholinesterase properties identified in a standardized ethanol extract of this species [P. olacoides standardized ethanol extract (POEE)]. OBJECTIVES: To further characterize the potential of this extract for developing drugs useful to treat cognitive deficits, the effects of POEE on scopolamine (scop)- and MK801-induced amnesias (acquisition, consolidation, and retrieval) in mice were investigated. RESULTS: Scop (3.0 mg/kg, ip) significantly impaired memory (all three phases) in the step-down inhibitory avoidance protocol. As expected, MK801 (0.1 mg/kg, ip) was amnesic regarding acquisition and consolidation, but not retrieval. POEE (100 mg/kg, ip) reversed the scop-induced impairment in all three phases of long-term and short memories, whereas only the memory consolidation deficit was reversed with MK801-induced amnesia. CONCLUSIONS: This study complements previously reported promnesic properties of this plant extract and suggests that POEE may be further developed for treating conditions associated with cognitive deficits, especially those linked with cholinergic malfunction.

The putative antipsychotic alstonine reverses social interaction withdrawal in mice.

Negative symptoms of schizophrenia are particularly problematic due to their deleterious impact on a patient's social life. The indol alkaloid alstonine, the major component of traditional remedies used for treating mental illnesses in Nigeria, presents a clear antipsychotic-like profile in mice, as well as anxiolytic properties. Considering that social interaction is the core of negative symptoms, and that anxiolytic drugs can improve social interaction behavior, the aim of this study was to evaluate the effects of alstonine in the social interaction and MK801-induced social withdrawal models in mice. Sub-chronic (but not acute) treatment with alstonine 0.5 mg/kg (but not 1.0 mg/kg) significantly increased social interaction in mice. Moreover, MK801-induced social withdrawal was completely prevented by sulpiride (10 mg/kg) and alstonine 1.0 mg/kg, and partially prevented by alstonine 0.5 mg/kg. The study indicates that alstonine not only increases social interaction in normal mice, but also averts social deficits attributable to negative symptoms of schizophrenia. This study reinforces and complements the antipsychotic-like profile of alstonine, and emphasizes its potential as a drug useful for the management of negative symptoms in schizophrenia.