There are currently no pharmacological treatments for cocaine use disorder. Recently there has been a great deal of interest in the potential of psychedelic drugs such as psilocybin to treat psychiatric disorders. Human studies have indicated that a single administration of psilocybin can have long-lasting effects. Few preclinical studies have examined a role for psilocybin in addiction models. The goal of the current study was to determine whether psilocybin would enhance extinction following cocaine self-administration in male and female mice and rats and thus result in an attenuation of cue-induced drug-seeking. In experiments in mice, 16 female and 19 male mice underwent 8d of cocaine self-administration (0.5 mg/kg/infusion) and extinction training. Immediately following extinction trials, mice were injected with vehicle or 1.0 mg/kg psilocybin. Following the conclusion of extinction training, mice were tested for cue-induced reinstatement. In experiments in rats, 24 female and 23 male rats underwent 15d of cocaine self-administration (0.8 mg/kg/infusion) and extinction training. Immediately following extinction trials, rats were injected with vehicle, 1.0 mg/kg psilocybin, or 2.5 mg/kg psilocybin. Following the conclusion of extinction training, rats were tested for cue-induced reinstatement. Psilocybin administered following extinction trials had no effect, as both female and male mice and rats demonstrated significant cue-induced reinstatement. These data suggest that psilocybin is ineffective at altering cocaine-seeking behavior in the paradigm and doses used in the current study. It remains to be seen whether treatment with psilocybin under different conditions may be useful in the long-standing goal of finding pharmacotherapies to treat CUD.
- MeSH
- autoaplikace * MeSH
- chování při shánění drogy * účinky léků MeSH
- extinkce (psychologie) * účinky léků MeSH
- halucinogeny * farmakologie aplikace a dávkování MeSH
- inhibitory vychytávání dopaminu farmakologie aplikace a dávkování MeSH
- kokain * farmakologie aplikace a dávkování MeSH
- krysa rodu rattus MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- operantní podmiňování účinky léků MeSH
- podněty * MeSH
- pohlavní dimorfismus MeSH
- poruchy spojené s užíváním kokainu farmakoterapie psychologie MeSH
- potkani Sprague-Dawley MeSH
- psilocybin * farmakologie aplikace a dávkování MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Therapeutic options for Alzheimer's disease are limited. Dual compounds targeting two pathways concurrently may enable enhanced effect. The study focuses on tacrine derivatives inhibiting acetylcholinesterase (AChE) and simultaneously N-methyl-D-aspartate (NMDA) receptors. Compounds with balanced inhibitory potencies for the target proteins (K1578 and K1599) or increased potency for AChE (K1592 and K1594) were studied to identify the most promising pro-cognitive compound. Their effects were studied in cholinergic (scopolamine-induced) and glutamatergic (MK-801-induced) rat models of cognitive deficits in the Morris water maze. Moreover, the impacts on locomotion in the open field and AChE activity in relevant brain structures were investigated. The effect of the most promising compound on NMDA receptors was explored by in vitro electrophysiology. The cholinergic antagonist scopolamine induced a deficit in memory acquisition, however, it was unaffected by the compounds, and a deficit in reversal learning that was alleviated by K1578 and K1599. K1578 and K1599 significantly inhibited AChE in the striatum, potentially explaining the behavioral observations. The glutamatergic antagonist dizocilpine (MK-801) induced a deficit in memory acquisition, which was alleviated by K1599. K1599 also mitigated the MK-801-induced hyperlocomotion in the open field. In vitro patch-clamp corroborated the K1599-associated NMDA receptor inhibitory effect. K1599 emerged as the most promising compound, demonstrating pro-cognitive efficacy in both models, consistent with intended dual effect. We conclude that tacrine has the potential for development of derivatives with dual in vivo effects. Our findings contributed to the elucidation of the structural and functional properties of tacrine derivatives associated with optimal in vivo pro-cognitive efficacy.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- antagonisté excitačních aminokyselin farmakologie MeSH
- bludiště - učení * účinky léků MeSH
- cholinesterasové inhibitory * farmakologie MeSH
- dizocilpinmaleát * farmakologie MeSH
- kognice * účinky léků MeSH
- krysa rodu rattus MeSH
- paměť účinky léků MeSH
- potkani Wistar * MeSH
- receptory N-methyl-D-aspartátu * antagonisté a inhibitory metabolismus MeSH
- skopolamin MeSH
- takrin * farmakologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Radiomic features are usually used to predict target variables such as the absence or presence of a disease, treatment response, or time to symptom progression. One of the potential clinical applications is in patients with Parkinson's disease. Robust radiomic features for this specific imaging method have not yet been identified, which is necessary for proper feature selection. Thus, we are assessing the robustness of radiomic features in dopamine transporter imaging (DaT). For this study, we made an anthropomorphic head phantom with tissue heterogeneity using a personal 3D printer (polylactide 82% infill); the bone was subsequently reproduced with plaster. A surgical cotton ball with radiotracer (123I-ioflupane) was inserted. Scans were performed on the two-detector hybrid camera with acquisition parameters corresponding to international guidelines for DaT single photon emission tomography (SPECT). Reconstruction of SPECT was performed on a clinical workstation with iterative algorithms. Open-source LifeX software was used to extract 134 radiomic features. Statistical analysis was made in RStudio using the intraclass correlation coefficient (ICC) and coefficient of variation (COV). Overall, radiomic features in different reconstruction parameters showed a moderate reproducibility rate (ICC = 0.636, p <0.01). Assessment of ICC and COV within CT attenuation correction (CTAC) and non-attenuation correction (NAC) groups and within particular feature classes showed an excellent reproducibility rate (ICC > 0.9, p < 0.01), except for an intensity-based NAC group, where radiomic features showed a good repeatability rate (ICC = 0.893, p <0.01). By our results, CTAC becomes the main threat to feature stability. However, many radiomic features were sensitive to the selected reconstruction algorithm irrespectively to the attenuation correction. Radiomic features extracted from DaT-SPECT showed moderate to excellent reproducibility rates. These results make them suitable for clinical practice and human studies, but awareness of feature selection should be held, as some radiomic features are more robust than others.
Chronic treatment with acetylcholinesterase inhibitors may be a promising therapeutic strategy for treatment of cardiovascular diseases. The aim of our study was to analyze the changes in blood pressure (BP) and heart rate (HR) during 14 days of treatment with two different acetylcholinesterase inhibitors - pyridostigmine (PYR) having only peripheral effects or donepezil (DON) with both peripheral and central effects. In addition, we studied their effects on the cardiovascular response to restraint stress and on sympathovagal control of HR in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). SHR were characterized by elevated BP and increased low-frequency component of systolic BP variability (LF-SBPV), but their cardiac vagal tone and HR variability (HRV) were reduced compared with WKY. Chronic treatment with either acetylcholinesterase inhibitor decreased HR and increased HRV in both strains. PYR treatment slightly decreased BP and LF-SBPV in the dark phase of the day. Neither drug significantly altered BP response to stress, but PYR attenuated HR increase during restraint stress. Regarding sympathovagal balance, acute methylatropine administration caused a greater increase of HR in WKY than in SHR. Chronic PYR or DON treatment enhanced HRV and HR response to methylatropine (vagal tone) in WKY, whereas PYR but not DON treatment potentiated HRV and vagal tone in SHR. In conclusion, vagal tone was lower in SHR compared with WKY, but was enhanced by chronic PYR treatment in both strains. Thus, chronic peripheral, but not central, acetylcholinesterase inhibition has major effects on HR and its variability in both normotensive and hypertensive rats.
- MeSH
- acetylcholinesterasa MeSH
- cholinesterasové inhibitory farmakologie terapeutické užití MeSH
- deriváty atropinu * MeSH
- donepezil farmakologie MeSH
- hypertenze * farmakoterapie MeSH
- krevní tlak MeSH
- krysa rodu rattus MeSH
- potkani inbrední SHR MeSH
- potkani inbrední WKY MeSH
- pyridostigmin-bromid * farmakologie MeSH
- srdeční frekvence MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: Regular cocaine use has been associated with hormonal dysfunction including hypogonadism, which can lead to fatigue, reduced stamina, sexual dysfunction, and impaired quality of life. However, cocaine's endocrine effects are largely under-reported in the scientific addiction literature and, in many cases, are not addressed within treatment services. The low profile of these adverse effects might be attributable to a lack of awareness and linkage with cocaine use, such that they are recognized only when an acute/emergency problem arises. METHODS: We assessed endocrine diurnal function (adrenocorticotrophic hormone [ACTH], cortisol, and testosterone) in 26 healthy and 27 cocaine-dependent men and examined changes in hormone levels in response to a single 40 mg dose of the noradrenaline re-uptake inhibitor atomoxetine in a double-blind, placebo-controlled experimental medicine study. RESULTS: When compared with healthy controls, diurnal and atomoxetine-induced changes in ACTH and cortisol showed greater variability in cocaine-dependent men. Interestingly, despite an exaggerated rise in ACTH following atomoxetine, an attenuated cortisol response was observed, and one-third of cocaine-dependent men had subnormal testosterone levels. CONCLUSION: Our findings point to a potential disconnection between the pituitary and adrenal responses in cocaine-dependent men, a higher rate of hypogonadism, and a pressing need for more research into the endocrine effects of cocaine and their clinical implications.
- MeSH
- adrenokortikotropní hormon MeSH
- atomoxetin farmakologie MeSH
- hydrokortison MeSH
- hypogonadismus * MeSH
- kokain * MeSH
- kvalita života MeSH
- lidé MeSH
- poruchy spojené s užíváním kokainu * MeSH
- poruchy spojené s užíváním psychoaktivních látek * MeSH
- systém hypofýza - nadledviny MeSH
- systém hypotalamus-hypofýza MeSH
- testosteron MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- randomizované kontrolované studie MeSH
- zprávy MeSH
Cyanobacterial blooms are increasing in frequency and intensity globally, and impacting recreational waters as well as waters used for drinking water provisioning. They are sources of bioactive metabolites including retinoids and the neurotoxin anatoxin-a. Here, we investigated the effects of anatoxin-a on a differentiating in vitro human neural stem cell model previously characterised with retinoic acids. Effects on protein and gene expression upon exposure for 9 or 18 days to anatoxin-a alone or in co-exposure with all-trans retinoic acid were evaluated using a panel of neural and glial differentiation biomarkers. Anatoxin-a did not cause distinct developmental neurotoxicity alone, or in co-exposure with retinoic acid. However, in line with its excitotoxicity, in co-exposure with 200 nM all-trans retinoic acid it reduced the differentiation of acetylcholinergic neuron subtypes in the culture at 1000 nM (highest tested concentration). While this could have substantial functional implications for the developing nervous system, there is no indication for developmental neurotoxicity beyond its (excito-)toxicity to acetylcholinergic neurons, which only occurred in co-exposure to all-trans retinoic acid.
- MeSH
- exprese genu MeSH
- lidé MeSH
- neurotoxické syndromy * etiologie MeSH
- retinoidy metabolismus MeSH
- sinice * MeSH
- toxiny kmene Cyanobacteria MeSH
- tretinoin toxicita MeSH
- tropany * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Introduction: Spasm of the near reflex usually includes accommodative spasm, esophoria/tropia, and different degrees of miosis. Patients usually refer to distance blurred and fluctuating vision, ocular discomfort, and headaches. The diagnosis is established with refraction with and without cycloplegia; most of the cases have a functional etiology. However, some cases require neurological conditions to be ruled out; cycloplegics have an important diagnostic and therapeutic role. Purpose: To describe a case of bilateral severe accommodative spasm in a healthy 14-year-old teenager. Case presentation: A 14-year-old boy with progressive diminished visual acuity attended for YSP consultation. The diagnosis of bilateral spasm of the near reflex was made, based on a gap refraction of 9.75 D between retinoscopy with and without cycloplegia and esophoria with normal keratometry and axial length. The spasm was eliminated with 2 drops of cycloplegic in each eye separated by 15 days; no clear etiology was found other than the start of school. Conclusion: Clinicians should be aware of pseudomyopia, especially in children with acute changes in visual acuity, who are usually exposed to myopigenic environmental factors that induce overstimulation of the parasympathetic third cranial nerve’s innervation.
- MeSH
- akomodace oka * MeSH
- atropin aplikace a dávkování terapeutické užití MeSH
- esotropie diagnóza etiologie MeSH
- lidé MeSH
- mladiství MeSH
- mydriatika MeSH
- reflex fyziologie MeSH
- refrakce oka MeSH
- spasmus farmakoterapie patofyziologie MeSH
- Check Tag
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Organophosphorus nerve agents pose a global threat to both military personnel and civilian population, because of their high acute toxicity and insufficient medical countermeasures. Commonly used drugs could ameliorate the intoxication and overall medical outcomes. In this study, we tested the drugs able to alleviate the symptoms of Alzheimer's disease (donepezil, huperzine A, memantine) or Parkinson's disease (procyclidine). They were administered to mice before soman intoxication in terms of their: i) protection potential against soman toxicity and ii) influence on post-exposure therapy consisting of atropine and asoxime (also known as oxime HI-6). Their pretreatment effect was not significant, when administered alone, but in combination (acetylcholinesterase inhibitor such as denepezil or huperzine A with NMDA antagonist such as memantine or procyclidine) they lowered the soman toxicity more than twice. These combinations also positively influenced the efficacy of post-exposure treatment in a similar fashion; the combinations increased the therapeutic effectiveness of antidotal treatment. In conclusion, the most effective combination - huperzine A and procyclidine - lowered the toxicity three times and improved the post-exposure therapy efficacy more than six times. These results are unprecedented in the published literature.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- antidota terapeutické užití MeSH
- atropin terapeutické užití farmakologie MeSH
- cholinesterasové inhibitory toxicita MeSH
- jedy * MeSH
- memantin terapeutické užití MeSH
- míra přežití MeSH
- myši MeSH
- oximy terapeutické užití farmakologie MeSH
- procyklidin farmakologie MeSH
- pyridinové sloučeniny farmakologie MeSH
- receptory N-methyl-D-aspartátu MeSH
- soman * toxicita MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Cocaine- and amphetamine-regulated transcript peptide (CARTp) is an anorexigenic neuropeptide whose receptor is undisclosed. Previously, we reported the specific binding of CART(61-102) to pheochromocytoma PC12 cells, where CART(61-102) affinity and the number of binding sites per cell corresponded to ligand-receptor binding. Recently, Yosten et al. designated orphan GPR160 as the CARTp receptor, because the GPR160 antibody abolished neuropathic pain and anorexigenic effects induced by CART(55-102) and exogenous CART(55-102) coimmunoprecipitated with GPR160 in KATOIII cells. As no direct evidence that CARTp is a ligand for GPR160 has been described, we decided to verify this hypothesis by testing CARTp affinity to the GPR160 receptor. We investigated the GPR160 expression in PC12 cells since it is cell line known to specifically bind CARTp. Moreover, we examined the specific CARTp binding in THP1 cells, with high endogenous GPR160 expression and GPR160-transfected cell lines U2OS and U-251 MG. In PC12 cells, the GPR160 antibody did not compete for specific binding with 125I-CART(61-102) or with 125I-CART(55-102), and GPR160 mRNA expression and GPR160 immunoreactivity were not detected. Moreover, THP1 cells did not show any 125I-CART(61-102) or 125I-CART(55-102) specific binding despite GPR160 detection by fluorescent immunocytochemistry (ICC). Finally, no 125I-CART(61-102) or 125I-CART(55-102) specific binding in the GPR160-transfected cell lines U2OS and U-251 MG, selected due to their negligible endogenous expression of GPR160, was detected, despite the detection of GPR160 by fluorescent ICC. Our binding studies clearly demonstrated that GPR160 cannot be a receptor for CARTp. Further studies are needed to identify true CARTp receptors.
- MeSH
- kokain * MeSH
- krysa rodu rattus MeSH
- ligandy MeSH
- proteiny nervové tkáně * genetika metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
