MDPV (3,4-methylenedioxypyrovalerone) administered to mice during development of the central nervous system produces persistent learning and memory impairments.

BACKGROUND: Synthetic cathinones (SC) constitute the second most frequently abused class of new psychoactive substances. They serve as an alternative to classic psychostimulatory drugs of abuse, such as methamphetamine, cocaine, or 3,4-methylenedioxymethamphetamine (MDMA). Despite the worldwide prevalence of SC, little is known about their long-term impact on the central nervous system. Here, we examined the effects of repeated exposure of mice during infancy, to 3,4-methylenedioxypyrovalerone (MDPV), a SC potently enhancing dopaminergic neurotransmission, on learning and memory in young adult mice. METHODS: All experiments were performed on C57BL/6J male and female mice. Animals were injected with MDPV (10 or 20 mg/kg) and BrdU (bromodeoxyuridine, 25 mg/kg) during postnatal days 11-20, which is a crucial period for the development of their hippocampus. At the age of 12 weeks, mice underwent an assessment of various types of memory using a battery of behavioral tests. Afterward, their brains were removed for detection of BrdU-positive cells in the dentate gyrus of the hippocampal formation with immunohistochemistry, and for measurement of the expression of synaptic proteins, such as synaptophysin and PSD95, in the hippocampus using Western blot. RESULTS: Exposure to MDPV resulted in impairment of spatial working memory assessed with Y-maze spontaneous alternation test, and of object recognition memory. However, no deficits in hippocampus-dependent spatial learning and memory were found using the Morris water maze paradigm. Consistently, hippocampal neurogenesis and synaptogenesis were not interrupted. All observed MDPV effects were sex-independent. CONCLUSIONS: MDPV administered repeatedly to mice during infancy causes learning and memory deficits that persist into adulthood but are not related to aberrant hippocampal development.

Peat mine as a threat to the diversity of aquatic beetles (Coleoptera: Dytiscidae) in the protected area Nature 2000 in Poland.

Peatlands, shaped by centuries of human activities, now face a primary threat from mining activities. Vulnerable to drainage and hydrological instability, peatland areas encounter challenges that compromise their ecological integrity. This study hypothesised that permanent water reservoirs within mines could serve as refugia for water beetles from adjacent areas prone to drying in the summer. Employing standard methods, including entomological scraping and water traps, samples were collected. Results revealed that, in most cases, water beetles exhibited a preference for the Nature 2000 area untouched by mining. Despite unfavourable conditions, the Nature 2000 area showcased a more diverse water beetle fauna. Remarkably, the selected Nature 2000 area, despite its identified degradation based on flora, remained a biodiversity hotspot for peatland water beetle fauna. The study underscores the significance of assessing insects, particularly beetles, as rapid responders to environmental changes. This evaluation holds crucial implications for peatland restoration planning and decision-making regarding mining investments in proximity to peatland areas.

Outflows from lakes as ecotones - stable conditions maintain macroinvertebrates biodiversity.

Outflows from the lakes are rarely considered as an ecotones. The main research direction on invertebrates of lake outflows most often are functional feeding groups, especially filter-feeders as a dominant group in that environment. Our goal was to describe the biodiversity of macroinvertebrates in lake-river ecotones in lowlands of Central Europe, found the environmental factors that shape the biodiversity of that environment and indicate directions for further biodiversity conservation. 40 outflows from lakes with different parameters were selected for the research. During the research, 57 taxa were found at the study sites, of which 32 taxa reached a frequency at least 10 %. The Multiple linear regression showed only one significant relationships between fluvial model and biodiversity. Of the components of this model, only depth of the outflow correlated significantly. There was observed significant differences in the Shannon-Wiener index, which was significantly higher in deeper outflows. Depth of the outflow indirectly affects the preservation of the biodiversity of the ecotone, which results from the greater stability of the water conditions in this place. It should be pay special attention to the water conditions of the catchments in order to minimize water level fluctuations and their negative effect on biodiversity in lake-river ecotones.

Psychiatric and neurological complications of long COVID.

COVID-19 was primarily considered a pulmonary disease with extrapulmonary manifestations. As the pandemic spread, there has been growing evidence that the disease affects various organs/systems, including the central and peripheral nervous systems. Accumulation of clinical data demonstrates that in a large population of survivors impairments in the function of one or more organs may persist for a long time, a phenomenon commonly known as post COVID or long COVID. Fatigue and cognitive dysfunction, such as concentration problems, short-term memory deficits, general memory loss, a specific decline in attention, language and praxis abilities, encoding and verbal fluency, impairment of executive functions, and psychomotor coordination, are amongst the most common and debilitating features of neuropsychatric symptoms of post COVID syndrome. Several patients also suffer from compromised sleep, depression, anxiety and post-traumatic stress disorder. Patients with long COVID may demonstrate brain hypometabolism, hypoperfusion of the cerebral cortex and changes in the brain structure and functional connectivity. Children and adolescents represent a minority of COVID-19 cases, so not surprisingly data on the long-term sequelae after SARS-CoV-2 infections in these age groups are scarce. Although the pathogenesis, clinical characteristics, epidemiology, and risk factors of the acute phase of COVID-19 have been largely explained, these areas are yet to be explored in long COVID. This review aims to provide an update on what is currently known about long COVID effects on mental health.

Role of Chemokines in the Development and Progression of Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurogenerative disorder manifested by gradual memory loss and cognitive decline due to profound damage of cholinergic neurons. The neuropathological hallmarks of AD are intracellular deposits of neurofibrillary tangles (NFTs) and extracellular aggregates of amyloid ß (Aß). Mounting evidence indicates that intensified neuroinflammatory processes play a pivotal role in the pathogenesis of AD. Chemokines serve as signaling molecules in immune cells but also in nerve cells. Under normal conditions, neuroinflammation plays a neuroprotective role against various harmful factors. However, overexpression of chemokines initiates disruption of the integrity of the blood-brain barrier, facilitating immune cells infiltration into the brain. Then activated adjacent glial cells-astrocytes and microglia, release massive amounts of chemokines. Prolonged inflammation loses its protective role and drives an increase in Aß production and aggregation, impairment of its clearance, or enhancement of tau hyperphosphorylation, contributing to neuronal loss and exacerbation of AD. Moreover, chemokines can be further released in response to growing deposits of toxic forms of Aß. On the other hand, chemokines seem to exert multidimensional effects on brain functioning, including regulation of neurogenesis and synaptic plasticity in regions responsible for memory and cognitive abilities. Therefore, underexpression or complete genetic ablation of some chemokines can worsen the course of AD. This review covers the current state of knowledge on the role of particular chemokines and their receptors in the development and progression of AD. Special emphasis is given to their impact on forming Aß and NFTs in humans and in transgenic murine models of AD.

Carfentanil - from an animal anesthetic to a deadly illicit drug.

The use of novel synthetic opioids as recreational drugs has become a public health concern as they are implicated in numerous fatal intoxications across the world. Synthetic opioids have played a major role in the United States opioid crisis and may contribute to a similar opioid epidemic in Europe. The most prominent group of designer opioids consists of fentanyl and its analogues. At present, carfentanil is the most dangerous fentanyl derivative. It was recently detected as an adulterant to other illicit drugs and counterfeit pharmaceuticals, contributing to life-threatening hospital admissions and fatalities. Toxic exposure to carfentanil typically occurs through injection, insufflation or inhalation. Carfentanil produces similar pharmacotoxicological effects to other opioids. However, due to its extraordinary potency, reversing carfentanil-induced severe and recurring respiratory depression requires administration of multiple or higher than standard doses of naloxone. Toxicological reports indicate that carfentanil use is strongly connected to polydrug use. Detection of carfentanil requires specific and sensitive analytical methods that are not commonly available in hospitals. Since abuse of carfentanil is an emerging problem, particularly in the United States, there is an urgent need to develop new techniques for rapid determination of intoxication evoked by this drug as well as new treatment regimens for effective overdose maintenance. This review presents current knowledge on pharmacological activity of carfentanil, prevalence and patterns of use, and analytical methods of its detection. Special emphasis is given to carfentanil-related non-fatal and lethal overdose cases.

Behavioral Effects of 4-CMC and 4-MeO-PVP in DBA/2J Mice After Acute and Intermittent Administration and Following Withdrawal from Intermittent 14-Day Treatment.

Synthetic cathinones appeared on the market in the 2000s as new psychoactive substances and gained significant prevalence among drug abusers. Cathinones produce psychostimulant and empathogenic effects by enhancing dopaminergic, noradrenergic, and serotoninergic neurotransmission in the brain, and those which potently and selectively enhance dopaminergic transmission are considered to have higher abuse potential. The present study examines the behavioral effects related to psychostimulant properties, abuse potential, and addiction in DBA/2J mice of two cathinones with different profile of action on monoamine system, 4-chloromethcathinone (4-CMC), and 4-methoxy-pyrrolidinopentiophenone (4-MeO-PVP). 4-CMC and 4-MeO-PVP increase spontaneous locomotor activity after acute treatment and produce behavioral sensitization after 7-day intermittent treatment, which is a common feature of drugs of abuse. 4-MeO-PVP, but not 4-CMC, produces conditioned place preference after 4 days, indicating its rewarding properties. Finally, the ability of 4-CMC and 4-MeO-PVP to induce withdrawal symptoms after discontinuation from 14-day treatment was assessed using a battery of tests for behavioral markers of depression in mice: a tail suspension test, a forced swim test, measuring despair, and a sucrose preference test, measuring anhedonia. None of the three tests revealed increased depressive symptoms. Moreover, neither spontaneous locomotor activity nor motor performance on a rotarod was impaired after 14-day treatment with the tested compounds. These results indicate that 14-day treatment of mice with 4-CMC or 4-MeO-PVP does not induce significant withdrawal symptoms after cessation, nor significant impairment of dopaminergic circuitry resulting in motor impairment. The current study shows that 4-CMC and 4-MeO-PVP produce abuse-related behavioral changes in mice, which are more pronounced after more dopamine-selective 4-MeO-PVP.

Emerging Role of Fentanyl in Antiplatelet Therapy.

Fentanyl is a potent synthetic opioid used to alleviate severe and chronic pain, as well as an adjunct to general or local anesthesia. Although fentanyl has been used for decades, its full effects are still unknown. Its analgesic and anesthetic activity arises from the stimulation of µ-opioid receptors, resulting in the inhibition of adenyl cyclase and downregulation of cyclic adenosine 3',5'-monophosphate (cAMP), as well as decreased calcium channel activity and increased potassium channel activity. The µ-opioid receptors are abundantly distributed within the central nervous system, where they mediate analgesia, and in the nerve cells of the intestines, where they regulate gastrointestinal tract motility in the secretion or transport of fluids and electrolytes. They are also expressed in blood cells, blood vessel cells, and skin. Given the widespread distribution of µ-opioid receptors, it is likely that fentanyl may also regulate the activity of many other cells, including platelets. Recent findings indicate that it may impair the action of ticagrelor: an oral P2Y12 receptor inhibitor acting as an antiplatelet drug. It could pose a risk of insufficient platelet inhibition and result in thrombotic complications in patients with coronary artery disease. This article tackles the issue of fentanyl interactions with antiplatelet drugs. The mechanism of this phenomenon is not fully understood. Similarly, the biological effects exerted by fentanyl on platelets and the presence of opioid receptors on the platelet surface remain an open question.

Four Synthetic Cathinones: 3-Chloromethcathinone, 4-Chloromethcathinone, 4-Fluoro-α-Pyrrolidinopentiophenone, and 4-Methoxy-α-Pyrrolidinopentiophenone Produce Changes in the Spontaneous Locomotor Activity and Motor Performance in Mice with Varied Profiles.

Two chloromethcathinones, 3-chloromethcathinone (3-CMC) and 4-chloromethcathinone (4-CMC), and two para-substituted α-pyrrolidinophenones, 4-methoxy-α-pyrrolidinopentiophenone (4-MeO-PVP) and 4-fluoro-α-pyrrolidinopentiophenone (4-F-PVP), represent synthetic cathinones, the second most frequently abused group of new psychoactive substances (NPSs), which has aroused a worldwide health concern in the last decade. Synthetic cathinones act as psychostimulants by elevating extracellular levels of monoaminergic neurotransmitters. This study investigates effects of 3-CMC, 4-CMC, 4-MeO-PVP, and 4-F-PVP on the spontaneous locomotor activity and motor performance of mice. Additionally, neurotoxicity of substituted methcathinones against SH-SY5Y neuroblastoma cells was evaluated. All test cathinones stimulate in a dose-dependent manner horizontal locomotor activity of mice. Consistently to our prior findings, pyrrovalerones, but not methcathinone derivatives, produce dose-dependent elevation of vertical locomotor activity (rearing behavior). None of the tested compounds decreases the time spent on the accelerating rotarod, pointing to the lack of considerable motor disability in mice after acute exposition. Only 4-MeO-PVP at the high tested dose (20 mg/kg) increases motor performance of mice. Considering that α-pyrrolidinophenones are highly potent and selective DA uptake inhibitors, while chloromethcathinones enhance non-selective DA/5-HT release, we suggest that the increase of vertical locomotor activity and performance on rotarod in mice may serve as a behavioral indicator of the monoaminergic profile of synthetic cathinones. Finally, this study gives first insights into cytotoxicity of both 3-CMC and 4-CMC displayed against SH-SY5Y cells, which emerges and intensifies after prolonged incubation, suggesting the indirect mechanism of action, unrelated to interactions with monoamine transporters.

Abuse of fentanyl: An emerging problem to face.

Fentanyl is a potent synthetic opioid used as a narcotic analgesic supplement in general and regional anesthesia as well as in management of persistent, severe chronic pain. Alarming epidemiological and forensic medicine reports, accumulated mainly during the last two decades, point to a growing increase in illicit use of fentanyl, mainly in North America and Europe. Toxicological data indicates that fentanyl use is inextricably linked with polydrug use. There are two main sources of fentanyl on the "recreational" drug market. First, the most common, combines illicitly manufactured fentanyl from clandestine sources. The drug is often mixed up with heroin ("fake heroin") to increase its potency at a little cost, or included in cocaine products. It can also be mixed into and sold as oxycodone-, hydrocodone- or alprazolam-containing tablets. The other way to gain fentanyl is through the diversion of fentanyl-containing medicines, especially transdermal patches (FTPs). Fentanyl extracted from FTP can be administered intravenously, insufflated or inhaled after volatilization. The drug can also be delivered by oral or transmucosal application of the whole patch, or by rectal insertion. The most common overdose symptoms are coma, lethargy, respiratory depression and arrest. Although naloxone, an opioid receptor antagonist, is the standard drug for fentanyl overdose rescue, attempts to revive patients with naloxone could be unsuccessful, due to the rapid onset of fentanyl's action. As the fentanyl problem is constantly growing, there is an urgent need for new, effective harm-reduction strategies and technologies, as well as overdose maintenance.