Antagonists of the stress and opioid systems restore the functional connectivity of the prefrontal cortex during alcohol withdrawal through divergent mechanisms.

Chronic alcohol consumption leads to dependence and withdrawal symptoms upon cessation, contributing to persistent use. However, the brain network mechanisms by which the brain orchestrates alcohol withdrawal and how these networks are affected by pharmacological treatments remain elusive. Recent work revealed that alcohol withdrawal produces a widespread increase in coordinated brain activity and a decrease in modularity of the whole-brain functional network using single-cell whole-brain imaging of immediate early genes. This decreased modularity and functional hyperconnectivity are hypothesized to be novel biomarkers of alcohol withdrawal in alcohol dependence, which could potentially be used to evaluate the efficacy of new medications for alcohol use disorder. However, there is no evidence that current FDA-approved medications or experimental treatments known to reduce alcohol drinking in animal models can normalize the changes in whole-brain functional connectivity. In this report, we tested the effect of R121919, a CRF1 antagonist, and naltrexone, an FDA-approved treatment for alcohol use disorder, on whole-brain functional connectivity using the cellular marker FOS combined with graph theory and advanced network analyses. Results show that both R121919 and naltrexone restored the functional connectivity of the prefrontal cortex during alcohol withdrawal, but through divergent mechanisms. Specifically, R121919 increased FOS activation in the prefrontal cortex, partially restored modularity, and normalized connectivity, particularly in CRF1-rich regions, including the prefrontal, pallidum, and extended amygdala circuits. On the other hand, naltrexone decreased FOS activation throughout the brain, decreased modularity, and increased connectivity overall except for the Mu opioid receptor-rich regions, including the thalamus. These results identify the brain networks underlying the pharmacological effects of R121919 and naltrexone and demonstrate that these drugs restored different aspects of functional connectivity of the prefrontal cortex, pallidum, amygdala, and thalamus during alcohol withdrawal. Notably, these effects were particularly prominent in CRF1- and Mu opioid receptors-rich regions highlighting the potential of whole-brain functional connectivity using FOS as a tool for identifying neuronal network mechanisms underlying the pharmacological effects of existing and new medications for alcohol use disorder.

Looking to the Future: Drug Delivery and Targeting in the Prophylaxis and Therapy of Severe and Chronic Diseases.

High molecular weight actives and cell-based therapy have the potential to revolutionize the prophylaxis and therapy of severe diseases. Yet, the size and nature of the agents - proteins, nucleic acids, cells - challenge drug delivery and thus formulation development. Moreover, off-target effects may result in severe adverse drug reactions. This makes delivery and targeting an essential component of high-end drug development. Loading to nanoparticles facilitates delivery and enables targeted mRNA vaccines and tumor therapeutics. Stem cell therapy opens up a new horizon in diabetes type 1 among other domains which may enhance the quality of life and life expectancy. Cell encapsulation protects transplants against the recipient's immune system, may ensure long-term efficacy, avoid severe adverse reactions, and simplify the management of rare and fatal diseases.The knowledge gained so far encourages to widen the spectrum of potential indications. Co-development of the active agent and the vehicle has the potential to accelerate drug research. One recommended starting point is the use of computational approaches. Transferability of preclinical data to humans will benefit from performing studies first on validated human 3D disease models reflecting the target tissue, followed by studies on validated animal models. This makes approaching a new level in drug development a multidisciplinary but ultimately worthwhile and attainable challenge. Intense monitoring of the patients after drug approval and periodic reporting to physicians and scientists remain essential for the safe use of drugs especially in rare diseases and pave future research.

Ozone therapy improves early stages of osseointegration in ovariectomized rats

Abstract Objective the aim of this study was to analyze the influence of ozone therapy (OZN) on peri-implant bone repair in critical bones by installing osseointegrated implants in the tibia of ovariectomized rats. Methodology ovariectomy was performed on 30 Wistar rats, aged six months (Rattus novergicus), and, after 90 days, osseointegrated implants were installed in each tibial metaphysis. The study groups were divided into the animals that received intraperitoneal ozone at a concentration of 700 mcg/kg — OZ Group (n=15) — and a control group that received an intraperitoneal saline solution and, for this reason, was named the SAL group (n=15). The applications for both groups occurred during the immediate post-operative period on the 2nd, 4th, 6th, 8th, 10th, and 12th day post-surgery. At various stages (14, 42, and 60 days), the animals were euthanized, and tests were performed on their tibiae. These tests include histomorphometric and immunohistochemical analyses, computerized microtomography, sampling in light-cured resin for calcified sections, and confocal microscopy. The obtained data were then analyzed using One-way ANOVA and the Shapiro-Wilk, Kruskal-Wallis, and student t-tests (P<0.05). Results our findings indicate that the OZ group (3.26±0.20 mm) showed better cellular organization and bone neoformation at 14 days (SAL group, 0.90±1.42 mm) (P=0.001). Immunohistochemistry revealed that osteocalcin labeling was moderate in the OZ group and mild in the SAL group at 14 and 42 days post-surgery. The data from the analysis of calcified tissues (microtomography, histometric, and bone dynamism analysis) at 60 days showed no statistically significant differences between the groups (P=0.32). Conclusion it was concluded that ozone therapy anticipated the initial phases of the peri-implant bone repair process.

Combination therapy with bevacizumab and a CCR2 inhibitor for human ovarian cancer: An in vivo validation study.

BACKGROUND: Anti-angiogenic therapy with bevacizumab (BEV), an anti-VEGF antibody, plays a critical role in the treatment of ovarian cancer. However, despite an encouraging initial response, most tumors become resistant to BEV over time, and a new strategy that enables sustainable treatment using BEV is therefore needed. METHODS: To overcome the resistance to BEV in patients with ovarian cancer, we performed a validation study of combination therapy with BEV (10 mg/kg) and the CCR2 inhibitor BMS CCR2 22 (20 mg/kg) (BEV/CCR2i) using 3 consecutive patient-derived xenografts (PDXs) of immunodeficient mice. RESULTS: BEV/CCR2i demonstrated a significant effect of growth suppression in the BEV-resistant serous PDX and BEV-sensitive serous PDX compared with BEV (30.4% after the second cycle and 15.5% after the first cycle, respectively), and treatment cessation did not attenuate this effect. Tissue clearing and immunohistochemistry with an anti-α-SMA antibody suggested that BEV/CCR2i suppressed angiogenesis from the host mice more than BEV. In addition, human CD31 immunohistochemistry revealed that BEV/CCR2i decreased microvessels originating from the patients to a significantly greater degree than BEV. Regarding the BEV-resistant clear cell PDX, the effect of BEV/CCR2i was unclear during the first five cycles, but the following two cycles of increased-dose BEV/CCR2i (CCR2i 40 mg/kg) significantly suppressed tumor growth compared with BEV (28.3%) by inhibiting the CCR2B-MAPK pathway. CONCLUSIONS: BEV/CCR2i showed a sustained anticancer immunity-independent effect in human ovarian cancer that was more significant in serous carcinoma than in clear cell carcinoma.

In vitro effects of European and Latin-American medicinal plants in CYP3A4 gene expression, glutathione levels, and P-glycoprotein activity.

Many medicinal plants species from European -such as Artemisia absinthium, Equisetum arvense, Lamium album, Malva sylvestris, Morus nigra, Passiflora incarnata, Frangula purshiana, and Salix alba- as well as Latin American traditions -such as Libidibia ferrea, Bidens pilosa, Casearia sylvestris, Costus spicatus, Monteverdia ilicifolia, Persea americana, Schinus terebinthifolia, Solidago chilensis, Syzygium cumini, Handroanthus impetiginosus, and Vernonanthura phosphorica- are shortlisted by the Brazilian National Health System for future clinical use. However, they lack many data on their action upon some key ADME targets. In this study, we assess non-toxic concentrations (up to100 µg/ml) of their infusions for in vitro ability to modulate CYP3A4 mRNA gene expression and intracellular glutathione levels in HepG2 cells, as well as P-glycoprotein (P-gp) activity in vincristine-resistant Caco-2 cells (Caco-2 VCR). We further investigated the activation of human pregnane X receptor (hPXR) in transiently co-transfected HeLa cells and the inhibition of Gamma-glutamyl transferase (GGT) in HepG2 cells. Our results demonstrate L. ferrea, C. sylvestris , M. ilicifolia, P. americana, S. terebinthifolia, S. cumini, V. phosphorica, E. arvense, P. incarnata, F. purshiana, and S. alba can significantly increase CYP3A4 mRNA gene expression in HepG2 cells. Only F. purshiana shown to do so likely via hPXR activation. P-gp activity was affected by L. ferrea, F. purshiana, S. terebinthifolia, and S. cumini. Total intracellular glutathione levels were significantly depleted by exposure to all extracts except S. alba and S. cumini This was accompanied by a lower GGT activity in the case of C. spicatus, P. americana, S. alba, and S. terebinthifolia, whilst L. ferrea, P. incarnata and F. purshiana increased it. Surprisingly, S. cumini aqueous extract drastically decreased GGT activity (-48%, p < 0.01). In conclusion, this preclinical study shows that the administration of some of these herbal medicines causes in vitro disturbances to key drug metabolism mechanisms. We recommend active pharmacovigilance for Libidibia ferrea (Mart.) L. P. Queiroz, Frangula purshiana Cooper, Schinus terebinthifolia Raddi, and Salix alba L. which were able to alter all targets in our preclinical study.

An in silico-in vitro pipeline for drug cardiotoxicity screening identifies ionic pro-arrhythmia mechanisms.

BACKGROUND AND PURPOSE: Before advancing to clinical trials, new drugs are screened for their pro-arrhythmic potential using a method that is overly conservative and provides limited mechanistic insight. The shortcomings of this approach can lead to the mis-classification of beneficial drugs as pro-arrhythmic. EXPERIMENTAL APPROACH: An in silico-in vitro pipeline was developed to circumvent these shortcomings. A computational human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) model was used as part of a genetic algorithm to design experiments, specifically electrophysiological voltage clamp (VC) protocols, to identify which of several cardiac ion channels were blocked during in vitro drug studies. Such VC data, along with dynamically clamped action potentials (AP), were acquired from iPSC-CMs before and after treatment with a control solution or a low- (verapamil), intermediate- (cisapride or quinine) or high-risk (quinidine) drug. KEY RESULTS: Significant AP prolongation (a pro-arrhythmia marker) was seen in response to quinidine and quinine. The VC protocol identified block of IKr (a source of arrhythmias) by all strong IKr blockers, including cisapride, quinidine and quinine. The protocol also detected block of ICaL by verapamil and Ito by quinidine. Further demonstrating the power of the approach, the VC data uncovered a previously unidentified If block by quinine, which was confirmed with experiments using a HEK-293 expression system and automated patch-clamp. CONCLUSION AND IMPLICATIONS: We developed an in silico-in vitro pipeline that simultaneously identifies pro-arrhythmia risk and mechanism of ion channel-blocking drugs. The approach offers a new tool for evaluating cardiotoxicity during preclinical drug screening.

Patient-derived xenograft models of neuroendocrine prostate cancer.

In recent years, patient-derived xenografts (PDXs) have attracted much attention as clinically relevant models for basic and translational cancer research. PDXs retain the principal histopathological and molecular heterogeneity of their donor tumors and remain stable across passages. These characteristics allow PDXs to offer a reliable platform for better understanding cancer biology, discovering biomarkers and therapeutic targets, and developing novel therapies. A growing interest in generating neuroendocrine prostate cancer (NEPC) PDX models has been demonstrated, and such models have proven useful in several areas. This review provides a comprehensive summary of currently available NEPC PDX collections, encompassing 1) primary or secondary sites where patient samples were collected, 2) donor patients' treatment histories, 3) morphological features (i.e., small cell and large cell), and 4) genomic alterations. We also highlight suitable models for various research purposes, including identifying therapeutic targets and evaluating drug responses in models with specific genomic backgrounds. Finally, we provide perspectives on the current knowledge gaps and shed light on future applications and improvements of NEPC PDXs.

Xenograft Models of Ovarian Cancer for Therapy Evaluation.

The evaluation of novel treatment regimes in ovarian cancer, ranging from cytotoxic agents and targeted therapy to surgery, demands clinically relevant mouse models to mimic human disease. These more advanced preclinical models provide a tool to obtain robust data on the mechanism of action, cytotoxicity and therapeutic efficacy of newly emerging antitumor therapies.In this chapter, we describe how to generate ovarian cancer xenograft models through injection of human tumor cell lines in immunocompromised mice. Detailed methodological descriptions are provided for both the commonly applied subcutaneous model and the more technically challenging orthotopic tumor model that involves inoculation of cancer cells in the ovarian bursa. We demonstrate how to monitor tumor growth and metastases in orthotopic ovarian models through noninvasive optical imaging and the procedures for treatment strategy, including administration of test compounds and debulking surgery. We comment on the strengths, limitations, and procedural challenges associated with each of the models.

Effects of a new thyrotropic drug isolated from Potentilla alba on the male reproductive system of rats and offspring development.

BACKGROUND: The dysfunction of the thyroid gland is a common medical condition. Nowadays, patients frequently use medicinal herbs as complementary or alternative options to conventional drug treatments. These patients may benefit from treatment of thyroid dysfunctions with Potentilla alba L. preparations. While it has been reported that Potentilla alba preparations have low toxicity, nothing is known about their ability to affect reproductive functions in patients of childbearing age. METHODS: Male Wistar rats were orally treated with a thyrotrophic botanical drug, standardized Potentilla alba Dry Extract (PADE), at doses 8 and 40 times higher than the median therapeutic dose recommended for the clinical trials, for 60 consecutive days. Male Wistar rats receiving water (H2O) were used as controls. After completing treatment, half of the PADE-treated and control males were used to determine PADE gonadotoxicity, and the remaining half of PADE-treated and control males were mated with intact females. Two female rats were housed with one male for two estrus cycles. PADE effects on fertility and fetal/offspring development were evaluated. RESULTS: Herein, we report that oral treatment of male Wistar rats with PADE before mating with intact females instigated marked effects on male reproductive organs. Treatment significantly decreased the motility of the sperm and increased the number of pathological forms of spermatozoa. Additionally, a dose-dependent effect on Leydig cells was observed. However, these PADE effects did not significantly affect male fertility nor fetal and offspring development when PADE-treated males were mated with intact females. CONCLUSIONS: PADE treatment of male rates negatively affected sperm and testicular Leydig cell morphology. However, these changes did not affect male fertility and offspring development. It is currently not known whether PADE treatment may affect human male fertility and offspring development. Therefore, these results from an animal study need to be confirmed in humans. Results from this animal study can be used to model the exposure-response relationship and adverse outcomes in humans.

How Qualification of 3D Disease Models Cuts the Gordian Knot in Preclinical Drug Development.

Preclinical research struggles with its predictive power for drug effects in patients. The clinical success of preclinically approved drug candidates ranges between 3% and 33%. Regardless of the approach, novel disease models and test methods need to prove their relevance and reliability for predicting drug effects in patients, which is usually achieved by method validation. Nevertheless, validating all models appears unrealistic due to the variety of diseases. Thus, novel concepts are needed to increase the quality of preclinical research.Herein, we introduce qualification as a minimal standard to establish the relevance of preclinical models and test methods. Qualification starts with prioritizing and translating scientific requirements into technical parameters by quality function deployment. Qualified models use authenticated cells, which resemble the corresponding cells in humans in morphology and drug target expression. Moreover, disease models differ from normal models in the expression of relevant biomarkers. As a result, qualified test methods can discriminate effects of treatment standards and the effects of weakly effective or ineffective substances. Observer-blind readout, adequate data documentation, dropout inclusion, and a priori power studies are as crucial as realistic dosage regimens for qualified approaches. Here, we showcase the implementation of qualification. Adjusting the level of model complexity and qualification to three defined phases of preclinical research assures the optimal level of certainty at each step.In conclusion, qualification strengthens the researchers' impact by defining basic requirements that novel approaches must fulfill while still allowing for scientific creativity. Qualification helps to improve the predictive power of preclinical research. Applied to human cell-based models, qualification reduces animal testing, since only effective drug candidates are subjected to final animal testing and subsequently to clinical trials.

Head and neck cancer patient-derived xenograft models - A systematic review.

BACKGROUND: Patient-derived xenograft (PDX) involve the direct surgical transfer of fresh human tumor samples to immunodeficient mice. This systematic review aimed to identify publications of head and neck cancer PDX (HNC-PDX) models, describing the main methodological characteristics and outcomes. METHODS: An electronic search was undertaken in four databases, including publications having used HNC-PDX. Data were analyzed descriptively. RESULTS: 63 articles were yielded. The nude mouse was one most commonly animal model used (38.8 %), and squamous cell carcinoma accounted for the majority of HNC-PDX (80.6 %). Tumors were mostly implanted in the flank (86.3 %), and the latency period ranged from 30 to 401 days. The successful rate ranged from 17 % to 100 %. Different drugs and pathways were identified. CONCLUSION: HNC-PDX appears to significantly recapitulate the morphology of the original HNC and represents a valuable method in translational research for the assessment of the in vivo effect of novel therapies for HNC.

Evaluating the efficacy of enzalutamide and the development of resistance in a preclinical mouse model of type-I endometrial carcinoma.

Androgen Receptor (AR) signaling is a critical driver of hormone-dependent prostate cancer and has also been proposed to have biological activity in female hormone-dependent cancers, including type I endometrial carcinoma (EMC). In this study, we evaluated the preclinical efficacy of a third-generation AR antagonist, enzalutamide, in a genetic mouse model of EMC, Sprr2f-Cre;Ptenfl/fl. In this model, ablation of Pten in the uterine epithelium leads to localized and distant malignant disease as observed in human EMC. We hypothesized that administering enzalutamide through the diet would temporarily decrease the incidence of invasive and metastatic carcinoma, while prolonged administration would result in development of resistance and loss of efficacy. Short-term treatment with enzalutamide reduced overall tumor burden through increased apoptosis but failed to prevent progression of invasive and metastatic disease. These results suggest that AR signaling may have biphasic, oncogenic and tumor suppressive roles in EMC that are dependent on disease stage. Enzalutamide treatment increased Progesterone Receptor (PR) expression within both stromal and tumor cell compartments. Prolonged administration of enzalutamide decreased apoptosis, increased tumor burden and resulted in the clonal expansion of tumor cells expressing high levels of p53 protein, suggestive of acquired Trp53 mutations. In conclusion, we show that enzalutamide induces apoptosis in EMC but has limited efficacy overall as a single agent. Induction of PR, a negative regulator of endometrial proliferation, suggests that adding progestin therapy to enzalutamide administration may further decrease tumor burden and result in a prolonged response.

Patient-Derived Xenograft Models of Pancreatic Cancer: Overview and Comparison with Other Types of Models.

Pancreatic cancer (PC) is anticipated to be second only to lung cancer as the leading cause of cancer-related deaths in the United States by 2030. Surgery remains the only potentially curative treatment for patients with pancreatic ductal adenocarcinoma (PDAC), the most common form of PC. Multiple recent preclinical studies focus on identifying effective treatments for PDAC, but the models available for these studies often fail to reproduce the heterogeneity of this tumor type. Data generated with such models are of unknown clinical relevance. Patient-derived xenograft (PDX) models offer several advantages over human cell line-based in vitro and in vivo models and models of non-human origin. PDX models retain genetic characteristics of the human tumor specimens from which they were derived, have intact stromal components, and are more predictive of patient response than traditional models. This review briefly describes the advantages and disadvantages of 2D cultures, organoids and genetically engineered mouse (GEM) models of PDAC, and focuses on the applications, characteristics, advantages, limitations, and the future potential of PDX models for improving the management of PDAC.

Potential Therapies for Cerebral Edema After Ischemic Stroke: A Mini Review.

Stroke is the leading cause of global mortality and disability. Cerebral edema and intracranial hypertension are common complications of cerebral infarction and the major causes of mortality. The formation of cerebral edema includes three stages (cytotoxic edema, ionic edema, and vasogenic edema), which involve multiple proteins and ion channels. A range of therapeutic agents that successfully target cerebral edema have been developed in animal studies, some of which have been assessed in clinical trials. Herein, we review the mechanisms of cerebral edema and the research progress of anti-edema therapies for use after ischemic stroke.

Technological Advances in Preclinical Drug Evaluation: The Role of -Omics Methods.

Preclinical drug development is an essential step in the drug development process where the evaluation of new chemical entities occurs. In particular, preclinical drug development phases include deep analysis of drug candidates' interactions with biomolecules/targets, their safety, toxicity, pharmacokinetics, metabolism by use of assays in vitro and in vivo animal assays. Legal aspects of the required procedures are well-established. Herein, we present a comprehensive summary of current state-of-the art approaches and techniques used in preclinical studies. In particular, we will review the potential of new, -omics methods and platforms for mechanistic evaluation of drug candidates and speed-up of the preclinical evaluation steps.

Noninvasive Imaging for Assessment of the Efficacy of Therapeutic Agents for Hepatocellular Carcinoma.

Morphological imaging techniques are typically used in the anti-cancer drug efficacy evaluation process. However, these techniques can evaluate the therapeutic efficacy only when the tumor shows anatomic changes-usually at later stages, when the therapeutic effects are poor. In contrast, molecular imaging allows noninvasive monitoring of tumor growth, assessment of drug metabolism, and evaluation of therapeutic efficacy at the molecular and cellular levels. Multimodality molecular imaging, which combines the advantages of various imaging modalities, provides even more comprehensive therapeutic efficacy assessment in preclinical and clinical studies. This review provides an overview of molecular imaging evaluation of therapeutic efficacy of the anti-tumor drugs in hepatocellular carcinoma (HCC) both in preclinical and clinical research, which holds great promise in guiding HCC treatment into the era of precision medicine.

The effect of natural products in animal models of temporomandibular disorders

Abstract Treatment of temporomandibular disorders (TMD) is a challenge for health care professionals. Therefore, new approaches have been investigated, such as the use of natural products. Objective This systematic review aims to summarize the natural products used in treatment of experimental models of TMD. Methodology A systematic search was performed in the databases Medline, Web of Science, Scopus, Embase, SciELO, LILACS, and Scholar Google databases in January 2020, dating from their inception. Pre-clinical studies with natural products for intervention in experimental TMD were included. Two reviewers independently selected the studies, extracted the data, and evaluated the risk of bias. Results 17 records were selected, and 17 different natural products were found, including three lectins, three plants or algae extracts, three sulfated polysaccharides, three cocoa preparations, and five isolated compounds. Concerning the risk of bias, most studies lacked on randomization and blinding. Nociception induced by phlogistic agents was evaluated in most articles, and in five studies it was associated with analysis of inflammatory parameters. In order to investigate the mechanism of action of the natural products used, eight studies evaluated expression of neural or glial molecular markers. Conclusions 16 of 17 natural products found in this review presented positive results, showing their potential for treatment of TMD. However, the lack of methodological clarity can influence these results.

Discovery of Novel Therapeutics for Muscular Dystrophies using Zebrafish Phenotypic Screens.

The recent availability and development of mutant and transgenic zebrafish strains that model human muscular dystrophies has created new research opportunities for therapeutic development. Not only do these models mimic many pathological aspects of human dystrophies, but their small size, large clutch sizes, rapid ex utero development, body transparency, and genetic tractability enable research approaches that would be inconceivable with mammalian model systems. Here we discuss the use of zebrafish models of muscular dystrophy to rapidly screen hundreds to thousands of bioactive compounds in order to identify novel therapeutic candidates that modulate pathologic phenotypes. We review the justification and rationale behind this unbiased approach, including how zebrafish screens have identified FDA-approved drugs that are candidates for treating Duchenne and limb girdle muscular dystrophies. Not only can these drugs be re-purposed for treating dystrophies in a fraction of the time and cost of new drug development, but their identification has revealed novel, unexpected directions for future therapy development. Phenotype-driven zebrafish drug screens are an important compliment to the more established mammalian, target-based approaches for rapidly developing and validating therapeutics for muscular dystrophies.

Psilocybin lacks antidepressant-like effect in the Flinders Sensitive Line rat.

OBJECTIVE: Psilocybin is a serotonin receptor agonist with a therapeutic potential for treatment-resistant depression and other psychiatric illnesses. We investigated whether the administration of psilocybin had an antidepressant-like effect in a rat model of depression. METHODS: Using the Flinders Sensitive Line (FSL) rat model of depression, we assessed the antidepressant-like effect of psilocin and psilocybin, measured as a reduction in immobility time in the forced swim test (FST). We measured locomotor activity in an open field test (OFT) to control for stimulant properties of the drugs. We performed a set of experiments to test different doses, treatment paradigms, and timing of the tests in relation to the drug administration. RESULTS: Psilocin and psilocybin showed no effect on immobility, struggling, or swimming behaviour in the FST and no effect on locomotor activity in the OFT. FSL rats did show significantly more immobility than their control strain, the Flinders Resistant Line, as expected. CONCLUSION: Psilocin and psilocybin showed no antidepressant-like effect in the FSL rats, despite a positive effect in humans. This suggests that other animal models of depression and other behavioural tests may be more appropriate for translational studies in the effects of psilocybin.