bluuebunny/crossref_metadata_2025_split huggingface dataset:
Psychedelics Improve the Mental Health of Rats
Authors: Hibicke Meghan , Landry Alexus N , Talman Zoe K , Nichols Charles 
Published: June 2021

IntroductionPsilocybin has recently demonstrated profound efficacy to alleviate depression and anxiety in several clinical trials and has received Breakthrough Status by the FDA. Symptomatic relief after only one or two therapeutic treatments last for at least several months in the vast majority of individuals. It is unclear whether the persistent antidepressant and anxiolytic effects are a psychological integration of the subject's personal experience while under the influence of the drug, or are a consequence of neurochemical changes induced by psilocybin that correct abnormalities leading to a healthier brain state. To distinguish between these possibilities, we investigated the antidepressant and anxiolytic effects of psilocybin in a rat model of treatment resistant depression, Wistar‐Kyoto (WKY) rats. Rats do not, as we currently believe, have a sense of self to reflect upon during a psychedelic experience. Therefore, if the effects are purely psychological, psilocybin should not occasion long lasting therapeutic effects as are seen in humans.ObjectiveTo evaluate the long‐term effects of psychedelics on depressive‐like and anxiety‐like behaviors in a rat model of depression.MethodsTwo experiments were performed in which rats were administered a single bolus dose of saline or treatment in saline vehicle: psilocybin (1 mg/kg), lysergic acid diethylamide (LSD, 0.15 mg/kg), or ketamine (5.0 mg/kg) intraperitoneally at a volume of 1 mL/kg. Saline (experiment 1, n=8) and repeat measures psilocybin (experiment 1, n=8) groups were evaluated in the Forced Swim Test (FST) weekly for five weeks, and then the Evaluated Plus Maze (EPM) on the sixth week. Interval psilocybin (experiment 1, n=8), saline (experiment 2, n=6), LSD (experiment 2, n=6), and ketamine (experiment 2, n=6) were evaluated in the FST a single time on the fifth week, and then in the EPM on the sixth week. All measures were evaluated with one‐way ANOVA using Holm‐Sidak post hoc, or with t‐test as appropriate.ResultsRemarkably, we have found that a single treatment with psilocybin produces context‐dependent, long lasting antidepressant‐like (p=0.046, p=0.026, and p<0.0001) and anxiolytic effects (p=0.039) in male WKY rats as measured by the FST and EPM. We have also found that LSD, a related psychedelic, produces a long lasting antidepressant‐like effect in male WKY rats (p=0.003), while ketamine does not.ConclusionsThese results indicate that at least a substantial portion of the ability of psychedelics to produce long lasting therapeutic effects has a biological basis and can be studied in animal models.Support or Funding InformationThis work was supported by Eleusis, PBC.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The opioid receptor positive allosteric modulator BMS‐986187 enhances some, but not all, delta‐opioid receptor mediated behaviors
Authors: Jutkiewicz Emily M , Palleiko Benjamin A , Dripps Isaac J , Rice Kenner C 
Published: June 2021

Activation of the delta opioid receptor (DOR) by orthosteric agonists produces antinociception, antihyperalgesia, antidepressant‐like effects, and convulsions in animal models. Positive allosteric modulators (PAMs) bind to a receptor site distinct from the orthosteric binding site and can augment the activity of the endogenous system. Therefore, a DOR PAM could be an effective strategy for eliciting potential therapeutic effects without convulsions. To evaluate this hypothesis, we investigated the ability of the opioid receptor PAM BMS‐986187 to elicit DOR‐mediated behaviors in mice alone or in combination with the DOR orthosteric agonist SNC80 and evaluated the potential contribution of multiple opioid receptor subtypes to the observed behavioral effects. Antidepressant‐like effects were evaluated in the mouse forced swim test and convulsions were evaluated by continuous observation. The contribution of DORs and mu‐opioid receptors (MORs) was evaluated through pharmacological and genetic manipulation of the receptor subtypes. BMS‐986187 alone produced antidepressant‐like effects without convulsions. These antidepressant‐like effects were blocked by the DOR antagonist naltrindole and absent in DOR knockout mice, indicating a DOR‐mediated effect. The antidepressant‐like effects of BMS‐986187 were enhanced in MOR knockout mice and following betaFNA pretreatment, suggesting that activation of MORs functionally inhibited DOR‐mediated antidepressant‐like effects. BMS‐986187 increased the potency of the orthosteric DOR agonist SNC80 to decrease immobility in the forced swim test but not to elicit convulsions. In addition, SNC80, but not BMS‐986187, enhanced the convulsive effects of pentylenetetrazol. Overall, these findings suggest that BMS‐986187 has activity at DORs and MORs in vivo and enhances some, but not all, behavioral effects of DOR agonists.Support or Funding InformationThis work was funded in part by a Research Starter Grant from the PhRMA Foundation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
MDMA and Pavlovian Fear Memory: Dose‐Effect Analysis
Authors: Pantoni Madeline M , Anagnostaras Stephan G 
Published: June 2021

±3,4‐methylenedioxymethamphetamine (MDMA) is a recreational drug that is also being pursued as a therapeutic for PTSD and other mood and anxiety disorders. Despite strong evidence of its therapeutic potential, these pursuits are hindered by evidence that MDMA produces robust neurotoxicity and cognitive deficits at high doses. These findings, however, may not generalize to typical recreational or therapeutic use of low‐dose MDMA. To date, there is little research on the cognitive effects of low/moderate doses of MDMA (less than 3 mg/kg) – the doses that users typically take. In the present study, we examined the effects of MDMA on learning and memory across a range of doses using a Pavlovian fear conditioning paradigm. Hybrid C57BL/6Jx129S1/SvImJ mice were randomly assigned to groups by MDMA dose. Mice were trained on‐drug with a single tone‐shock pairing and then tested off‐drug one week later for long‐term context and tone fear memory. We assessed the effects of doses of 0.1 to 8 mg/kg MDMA relative to vehicle control on immediate memory and long‐term contextual and cued memory. With increasing interest in therapeutic uses of MDMA, this research will help determine if low doses are therapeutically viable in terms of adverse effects on learning and memory.Support or Funding InformationNIH/NIDA Grant DA020041 (Anagnostaras)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mice with Gnao1 G203R Gain‐of‐Function (GOF) Mutation Phenocopy Combined Movement Disorder and Seizures of Patients
Authors: Larrivee Casandra L , Feng Huijie , Leipprandt Jefferey , Dimireva Elena , Xie Huirong , Neubig Richard 
Published: June 2021

Patients with de novo mutations in the gene for Gao (GNAO1) exhibit either early infantile epileptic encephalopathy (EIEE17) or neurodevelopmental delay with involuntary movements (NEDIM). Gao is the a subunit of the most abundant heterotrimeric G protein in brain. As with other Gi/o family G proteins, it can signal directly to effectors or by release of free Gbg resulting in inhibition of adenylyl cyclase or modulation of Ca++ and K+ ion channels. Loss‐of‐Function (LOF) alleles in GNAO1 result in epilepsy while GOF mutations result in movement disorder with or without seizures. Here we report the first mouse model of a human GNAO1 encephalopathy. Heterozygous GOF mutant mice (Gnao1+/G203R) were created using CRISPR/Cas9 to determine whether they replicate the clinical pattern of children with de novo GNAO1+/G203R mutations who display epilepsy as well as severe choreoathetosis and dystonia. There was a striking sex difference in the observed phenotypes. Male Gnao1+/G203R mice displayed significant deficits in open field, Rotarod®, Digigait®, and grip strength assessments. Also, they had enhanced seizure susceptibility in pentylenetrazol (PTZ) kindling studies. None of these differences were seen in female mice. Unlike children with the GNAO1 G203R mutation, there were no obvious dystonic or choreoathetotic movements or postures at baseline. After administration of oxotremorine, however, male Gnao1+/G203R mice displayed more forelimb raising and hindlimb splaying than was observed in WT mice. This novel model phenocopies the combined epilepsy and movement disorder phenotype of children with GNAO1 G203R mutations. These mice should facilitate studies of neural mechanisms and permit preclinical drug repurposing.Support or Funding InformationSupported by grants from the MSU Clinical and Translational Science Institute and The Bow Foundation.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Bimolecular modeling and simulation of antagonist binding to the alpha‐1A adrenergic receptor
Authors: O'Connell Timothy D , Aragon Ingrid R , Healy Chastity L , Muthyala Ramaiah , Sham Yuk 
Published: June 2021

Benign prostatic hyperplasia (BPH), which is a noncancerous enlargement of the prostate, currently affects 70% of men 60–69 years old, and 80% of men 70 years and older. By 2030, BPH incidence is predicted to increase based on the aging US population, and estimates suggest 20 million men 65 years and older will be diagnosed with BPH. BPH symptoms include frequent urination, difficulty initiating, maintaining, or a weak stream during urination, as well as inability to urinate or loss of bladder control. α1‐Adrenergic receptors (α1‐ARs), and particularly the α1A‐subtype, are highly expressed in prostate smooth muscle cells and mediate contraction. Clinically, α1‐AR antagonists, or α1‐blockers, are the primary treatment BPH with lower urinary tract symptoms (LUTS), including tamsulosin, touted as an α1A‐subtype selective antagonist. Here, our goal was to understand the molecular forces governing α1‐blocker binding to α1‐ARs to better understand α1‐blocker pharmacology. We have developed a homology model of α1‐antagonist binding to the α1A‐AR to identify essential molecular parameters that can be exploited for structure‐based drug design. Through homology modeling, docking, and molecular dynamics simulation, our preliminary model complex suggests for the first time 1) the burial of the terminal aromatic core within the hydrophobic pocket α1A‐AR and 2) the salt bridge interaction between its charged ammonium group with ionized aspartate are essential for ligand binding. This finding provides invaluable insight into design of the next generation, subtype‐specific of novel a1‐blockers.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A Docking‐Based Virtual Screen for Bifunctional μ‐Opioid Agonist/δ‐Opioid Antagonist Compounds
Authors: Chan Wallace , Zhang Yang , Traynor John 
Published: June 2021

The opioid receptors are family of G protein‐coupled receptors responsible for the modulation of pain, motor control, and mood. Opioid drugs, such as morphine, typically target the mu opioid receptor to elicit analgesia. However, a plethora of side effects, such as respiratory depression and addiction, manifest alongside their use, limiting their effectiveness in the long term. With the opioid crisis in our midst, the need for the development of a safer opioid with fewer or no side effects for pain management is of utmost importance. Recently, “mixed‐efficacy” bifunctional compounds acting as mu opioid receptor (MOR) agonists and delta opioid receptor (DOR) antagonists have been developed and shown in animal studies to produce analgesia with less potential for the development of tolerance and dependence. Consequently, the discovery of novel scaffolds for such compounds could lead to the development of safer opioid analgesics. Here, we report the development and validation of a sequential ligand‐ and structure‐based virtual screening pipeline. A ligand‐based virtual screen was used to establish an opioid‐enriched, targeted database for subsequent docking with AutoDock Vina. Retrospective virtual screening against a docking‐based benchmark dataset resulted in enrichment factor values from 7.8‐fold to over 10‐fold over random for both MOR and DOR, respectively, validating the efficacy of the model. In a prospective virtual screen, over 13 million compounds from the drug‐like subset of compounds in the ZINC database were screened, after which 360 unique compounds chemically dissimilar to currently‐known opioids were selected by manual inspection or clustering. Experimental validation of high‐scoring candidate compounds is underway to determine affinity and efficacy at MOR and DOR, and selectivity over other receptors.Support or Funding InformationDiscovery of New Treatments for Drug Abuse. Husbands, Stephen. Traynor, John. National Institute of Health (NIH). National Institute on Drug Abuse (NIDA). Project #: 5R01DA007315‐24This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
In Vitro Evaluation of Cimetidine Reno‐protective Effects on Cisplatin‐Induced Kidney Injury
Authors: Mody Hardik , Vaidya Tanaya , Lesko Lawrence , Ait‐Oudhia Sihem 
Published: June 2021

ObjectivesCisplatin (CIS), a platinum‐based drug, is one of the most efficacious anti‐cancer agents prescribed for a variety of solid tumors. However, CIS‐induced kidney injury (CIKI) remains a clinical challenge. The Organic Cation Transporter 2 (OCT2) is an uptake transporter predominantly expressed in the kidney proximal tubule cells. OCT2 is responsible for the cellular uptake of CIS by kidney cells. Our study aims to evaluate and quantify the in vitro renotoxicity effect of CIS and the reno‐protective effect of cimetidine (CIM), an OCT2 inhibitor, against CIKI.MethodsHuman renal proximal tubular epithelial cells, SA7K, were exposed for 72 hours to a range of concentrations of CIS (1–100 μM), CIM (0.1–2 mM), or to at least 12 different combinations of the two drugs. The inhibition of cellular viability was measured at 0, 12, 24, 48, and 72 hours using a CCK‐8 cellular viability kit. CIKI was captured with CIS stimulation of apoptosis in SA7K cells. CIM action on SA7K cells was fixed to the control (no treatment) baseline value. The combination of CIM with CIS was characterized with a competitive antagonism model using the Gaddum equation. Mathematical modeling was performed using Monolix (2016R1). All estimated parameters were determined as mean±SE.ResultsA dose‐dependent pattern in CIS toxicity on SA7K cells and CIM protection from CIKI is observed. The first‐order rate constant for SA7K cells death was estimated at 0.0047±0.00024 h−1. The maximal effect of CIS on CIKI (Smax) was determined at 0.07±0.0064 h−1, while CIS concentration inducing 50% of Smax was estimated at 70.3±10.5 μM. The concentration of CIM leading to 50% of Smax was determined at 486.3±69.8 μM. All time course profiles of cell viability responses to the single agents and combinations of CIS with CIM were described with our developed models.ConclusionsThe combination of CIM with CIS was successfully evaluated in vitro. The competitive antagonism model adequately captured the reno‐protective effects of CIM against CIKI. Further studies are in progress to investigate the molecular mechanisms underlying the beneficial effects of CIM on CIKI.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Pharmacological Properties of Artemisia monosperma (Del.)
Authors: Abu‐Niaaj Lubna F. , Katampe Ibrahim , Abdulla Shtaywy 
Published: June 2021

Plants are rich in secondary metabolites reputed for their pharmacological properties. With demands for bioactive compounds of natural origin, the attention is on commercializing the use of plants for pharmaceutical benefits. Our focus in on defining the biological activities of plants reputed in folk medicine to treat illnesses. We have been focusing on studying Artemisia monosperma to evaluate its potential usage for therapeutic uses. A. monosperma is a desert plant commonly known as an antispasmodic herb. We report that the boiled aqueous extract showed a concentration‐dependent antispasmodic effect of rat smooth muscle of ileum, pulmonary artery and uterus. The effect induced on the tracheal muscle was minimal while the contractile activity of the urinary bladder muscle was not affected. The activity of the cardiac muscle was inhibited upon addition of the aqueous extract which caused a decreased the rat heart rate accompanied by an increased in the contractile activity. This effect was reversible upon removal of the extract. Among compounds identified from A. monosperma, three flavonoids (arcapillin, eupatilin,7‐O‐Methyleriodictyol) showed a concentration‐dependent (10−7M −3×10−4 M) antispasmodic effect on rat smooth muscle of ileum, uterus and pulmonary artery. Only eupatilin and 7‐O‐Methyleriodictyol inhibited the contraction of trachea and urinary bladder. Further evaluation of the physiological effect of eupatilin on cardiac muscle showed that low concentrations (10−6 M and 10−5 M) caused an increase in the magnitude of cardiac muscle contraction accompanied by a decrease in heart rate which was followed by a partial heart blockage. At a concentration of 10−4M, the heart rate was reduced significantly leading to irreversible death of the infused heart. Eupatilin toxicity was determined by the median lethal dose (LD50) over 48hours on albino mice which came up to 31.8mg/kg. These finding indicate the importance of A. monosperma as a source for bioactive compounds of therapeutic significance.Support or Funding InformationSpecial thanks to Central State University and the University of Jordan for the technical support.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Identification of Covalent Modifications Derived from the GSTZ1‐catalyzed Metabolism of Dichloroacetate
Authors: Squirewell Edwin , Zhong Guo , James Margaret 
Published: June 2021

Glutathione transferase zeta 1 (GSTZ1) is a cytosolic and mitochondrial enzyme with a critical role in tyrosine catabolism via its trans‐isomerization of maleylacetoacetate (MAA) and maleylacetone (MA). Dichloroacetate (DCA) is an investigational drug utilized in the treatment of acquired and congenital mitochondrial diseases. Dechlorination of DCA to its inactive metabolite, glyoxylate, is catalyzed by GSTZ1, and allelic variants within GSTZ1 affect the kinetics of DCA conversion. DCA is a mechanism‐based inactivator of GSTZ1, and chronic DCA dosing results in the auto‐inhibition of DCA metabolism. The tissue accumulation of DCA, MAA, and MA due to GSTZ1 degradation may contribute to the observed side effects of DCA, as chronic dosing can lead to the development of reversible peripheral neuropathy in some patient populations. The mechanism for DCA‐induced inactivation of GSTZ1 is postulated to proceed via the formation of a carbonium‐sulfonium intermediate derived from the GSTZ1‐catalyzed reaction of glutathione and DCA. The intermediate may react with nucleophilic sites on GSTZ1 to yield covalently‐modified enzyme or undergo hydrolysis to form glyoxylate. Modification to Cys‐16 within the 14SSCSWR19 glutathione binding motif of GSTZ1 has been described as a mechanism of DCA inactivation, although the mechanism for haplotype differences remain unclear. Therefore, we examined multiple GSTZ1 isoforms for variations in covalent modifications derived from DCA metabolism. GSTZ1 haplotypes 1B, 1C, and 1D (0.5 mg, each) were incubated for 10 hours at 37C in the presence of 2 mM DCA, 5 mM GSH, and 1 mg/mL BSA as stabilizer. The precipitates were collected by centrifugation and separated via SDS‐PAGE to isolate bands for GSTZ1, which were then excised and subjected to tryptic digestion for mass spectral characterization. We confirmed the addition of glyoxylate (+74 m/z) to multiple serine residues within GSTZ1 and present the following serine modifications: Ser‐47 (1C), Ser‐187 (1B and 1D), Ser‐188 (1C and 1D), and Ser‐202 (1B, 1C, and 1D). Each haplotype demonstrated a single adduct of +364 m/z to Cys‐205 within the peptide 193LLVLEAFQVSHPCR206. The change in mass is consistent with an adduct that contains a molecule of glutathione bound to the backbone of DCA, which we describe as S‐carboxy‐methylglutathione. This is a newly characterized modification for the DCA‐induced inactivation of GSTZ1. The incidence of S‐carboxy‐methylglutathione was low and its role in GSTZ1 inactivation has yet to be explored. DCA‐induced inactivation of GSTZ1 could be due, in part, to the aggregation of proteins covalently modified by glyoxylate, and the number of sites accessible to covalent linkages may vary between GSTZ1 haplotypes.Support or Funding InformationSupported in part by the US Public Health Service GM 099871This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.