[Retinoblastoma: genetic background, modern diagnostic methods and therapies]. / Siatkówczak: podloze genetyczne, nowoczesne metody diagnostyczne oraz terapeutyczne.

Retinoblastoma is the most common intraocular eye tumor of the pediatric age. It develops on account of a mutation on chromosome 13 in the 13q14 locus. New studies additionally demonstrated changes in the expression of other genes classified as oncogenes and suppressor genes. The tumor occurs in two forms--heritable (genetic) and non-heritable (non-genetic, sporadic). The most common clinical features of retinoblastoma are leucocoria and strabismus, however, they are not that specific because may also occur in several other eye diseases, such as Coats disease and toxocarosis. The diagnosis of retinoblastoma requires an indirect ophthalmoscopic examination. In addition, imaging techniques such as ultrasonography (USG), magnetic resonance imaging (MRI) and, less commonly, computer tomography (CT) are used. Biopsy is contraindicated because of the risk of spreading cancer cells to the adjacent tissues and possibility of a metastasis development. Currently, the stage of the disease and the therapy prognosis are classified by the International Intraocular Retinoblastoma Classification. At present, chemotherapy is the standard treatment of retinoblastoma. During the last decades new therapies have been introduced, such as transpupillary thermotherapy (TTT), cryotherapy, brachytherapy, limiting the use of teletherapy and the number of performed enucleations. Patients with therapy-induced remission of retinoblastoma should undergo routine examinations because of the increased risk of subsequent neoplasms and other possible complications.

Spice/K2 drugs--more than innocent substitutes for marijuana.

Smokeable herbal mixtures containing synthetic agonists of cannabinoid receptors, known under brand names such as Spice, K2 and Kronic, represent a relatively new type of designer psychoactive drugs that has recently emerged on the recreational drug market. Although the Spice packages are labelled 'not for human consumption' or 'for aromatherapy only' and declared to be purely herbal, these herbal mixtures produce cannabis-like effects after smoking. This review surveys the current state of knowledge regarding the pharmacological properties of synthetic cannabimimetics and the prevalence and pattern of their use. Special emphasis is given to the negative consequences of using these products, including, among others, hallucinations, psychoses with delusions, seizures, cardiovascular symptoms and acute kidney injury.

Salvia divinorum: from Mazatec medicinal and hallucinogenic plant to emerging recreational drug.

Salvia divinorum is a sage endemic to a small region of Mexico and has been traditionally used by the Mazatec Indians for divination and spiritual healing. Recently, it has gained increased popularity as a recreational drug, used by adolescents and young adults as an alternative to marijuana and LSD. Salvinorin A, the major active ingredient of the plant, is considered to be the most potent known hallucinogen of natural origin. This review surveys the current state of knowledge on the neurochemical, pharmacokinetic, and pharmacological properties of salvinorin A, the trends and motivation behind S. divinorum use, and the health problems among users of the plant's products. S. divinorum induces intense, but short-lived, psychedelic-like changes in mood and perception, with concomitant hallucinations and disorientation. Many websites have misinterpreted the limited existing research-based information on the side effects of salvia as evidence for its safety. However, data accumulated over the last few years indicate that potential health risks are associated with the use of S. divinorum, especially by teenagers, users of other substances of abuse, and individuals with underlying psychotic disturbances. Taken together, the data presented in this review point to the need for further basic and clinical studies to create a basis for the development of well-addressed prevention and treatment strategies.

[Beta-cathinone derivatives--a new generation of dangerous psychostimulant "designer drugs"]. / Pochodne beta-katynonu--nowa generacja niebezpiecznych zwiazków psychostymulujacych z grupy "dopalaczy".

Synthetic beta-cathinone derivatives belong to the novel group of psychostimulant "designer drugs". They show significant structural similarity to catecholamines and exogenous central nervous system (CNS) stimulating agents such as amphetamine, methamphetamine, ephedrine, 3,4-methylenedioxy-N-methylamphetamine (MDMA, ecstasy), and act as dopamine, noradrenaline and serotonin reuptake inhibitors. Popular synthetic beta-cathinones include e.g. mephedrone (4-methylmethcathinone, 4-MMC), naphyrone (naphthylpyrovalerone) and MDPV (3,4-methylenedioxypyrovalerone). Ingestion of synthetic cathinones produces effects of CNS stimulation, often comparable to those evoked by cocaine, amphetamine and MDMA. Chronic abuse of beta-cathinone derivatives leads to the development of tolerance, psychic and physical dependence. This paper discusses pharmacological properties of the most commonly used beta-cathinone derivatives as well as risks associated with their abuse. Special emphasis is given to neurological, psychiatric, cardiovascular and hematologic disturbances. Authors also present cases of fatalities caused by acute beta-cathinone intoxication or resulting from the drug-related accidents and crimes.

Non-fentanyl new synthetic opioids - An update.

BACKGROUND: New synthetic opioids (NSO) constitute one of the fastest-growing group of New Psychoactive Substances, which emerged on the illicit drug marker in the second half of 2000's. The most popular and the largest NSO subgroup are high potency fentanyl and its analogs. Subsequent to core-structure scheduling of fentanyl-related substances many opioids with different chemical structures are now emerging on the illicit drug market, rendering the landscape highly complex and dynamic. METHODS: PubMed, Scopus and Google Scholar were searched for appropriate articles up to December 2022. Moreover, a search for reports was conducted on Institutional websites to identify documentation published by World Health Organization, United Nations Office on Drugs and Crime, United States Drug Enforcement Administration, and European Monitoring Centre for Drugs and Drug Addiction. Only articles or reports written in English were selected. RESULTS: Non-fentanyl derived synthetic opioids, i.e., 2-benzylbenzimidazoles (nitazenes), brorphine, U-compounds, AH-7921, MT-45 and related compounds are characterized, describing them in terms of available forms, pharmacology, metabolism as well as their toxic effects. Sample procedures and analytical techniques available for detection and quantification of these compounds in biological matrices are also presented. Finally, as overdoses involving highly potent NSO may be difficult to reverse, the effectiveness of naloxone as a rescue agent in NSO overdose is discussed. CONCLUSIONS: Current review presents key information on non-fentanyl derived NSO. Access to upto-date data on substances of abuse is of great importance for clinicians, public health authorities and professionals performing analyses of biological samples.

[Narcolepsy: etiology, clinical features, diagnosis and treatment]. / Narkolepsja: etiologia, obraz kliniczny, diagnostyka i leczenie.

 Narcolepsy is a chronic hypersomnia characterized by excessive daytime sleepiness (EDS) and manifestations of disrupted rapid eye movement sleep stage (cataplexy, sleep paralysis, and hypnagogic/hypnopompic hallucinations). Mechanisms underlying narcolepsy are not fully understood. Experimental data indicate that the disease is caused by a loss of hypocretin neurons in the hypothalamus, likely due to an autoimmune process triggered by environmental factors in susceptible individuals. Most patients with narcolepsy and cataplexy have very low hypocretin-1 levels in the cerebrospinal fluid. An appropriate clinical history, polysomnogram, and multiple sleep latency test are necessary for diagnosis of the disease. Additionally, two biological markers, i.e., cerebrospinal fluid hypocretin-1 levels and expression of the DQB1*0602 gene, are used. The treatment of narcolepsy is aimed at the different symptoms that the patient manifests. Excessive daytime sleepiness is treated with psychostimulants (amphetamine-like, modafinil and armodafinil). Cataplexy is treated with sodium oxybate (GHB), tricyclic antidepressants, or selective serotonin and noradrenaline reuptake inhibitors. Sleep paralysis, hallucinations, and fragmented sleep may be treated with sodium oxybate. Patients with narcolepsy should follow proper sleep hygiene and avoid strong emotions.

[Influence of the shift work on circadian-rhythms compare survey on health service employees and policemen]. / Wplyw pracy zmianowej na rytmy okolodobowe--badania porównawcze na pracownikach sluzby zdrowia i policjantach.

It has been estimating that about 20% working persons works in the shift system. It concerns health service employees and policemen among others. The shift work causes permanent conflict "of biological clock" with required working hours. The work in the night hours is less effective, it is held with greater expensive and triggering the increased tiredness.The aim of overtaken by the authors questionnaire survey amongst the population working in shifts, was to determining the influence of the shift work on the length and the quality of the dream and the tiredness and the sleepiness during day in comparison to group working only on the day shift. MATERIAL AND THE METHOD: The survey was conducted in the group of employees of the Health Service (30 persons) and policemen (20 persons) working in shifts. Healthy volunteers working in the system of the daily work constituted the control group (30 persons). The examination consisted of questionnaire forms which were filled in anonymously, the duration of examining one person lasted 4 weeks. RESULTS: Age and sex of the examined and control group were similar. In the examined period of time the number of night shift was averaged 6. During holidays 47 persons had night changes. Average time of dream was approximately 7 hours, for those who was working only at daily shift. On the following day after the night shift examined slept additionally average about 3 hours. Those who didn't work in shifts slept average 7.5 hour/24. Clinically significant sleeplessness was developed: examined group--18 persons, control group--3 persons. Amongst respondents we measured level of sleepiness during night shift using carolain scale of the sleepiness. Increase of sleepiness and decrease of activity appeared between 2:00 and 6:00 a.m. In the process of the examination a measurement of appearing the indications of exaggerated sleepiness and tiredness was also conducted using the ATS scale. The frequency of appearing was two or even three times bigger in the examined group. In examined group most common was reduction of psychophysical activity and difficulty in maintaining opened eyes. We have noted most often reduction of psychophysical activity and the problem with concentrating the eyesight on the object in the examined group. CONCLUSIONS: 1. The shift work is connected with a substantial effect to the clinical insomnia. 2. Insufficiency of sleep is a frequent occurrence in those who works in shifts especially having above 6 night shift monthly and also having children below 7 years.

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.

Use of fentanyl, butyrfentanyl and furanylfentanyl as discussed on Polish online forums devoted to 'designer drugs'. / Uzywanie fentanylu, butyrylofentanylu i furanylofentanylu w opinii uzytkowników polskich forów internetowych poswieconych "dopalaczom".

OBJECTIVES: The study was aimed to analyze information posted by users of synthetic opioids on Polish online drug discussion forums. Special emphasis was given to sources of drugs and their availability, routes of administration, dosages, expected and toxic effects. METHODS: 6,143 reports related to synthetic opioids, posted between 2005 and mid 2019 on three widely available popular Polish online forums devoted to psychoactive substances, i.e., hyperreal.info/talk, dopek.info and forum.dopalamy, were collected and analyzed. The article presents data on three most popular opioids, i.e., fentanyl, butyrfentanyl and furanylfentanyl. RESULTS: Fentanyl was the most widely used and relatively easily accessible synthetic opioid in Poland. Butyrfentanyl and furanylfentanyl were far less popular. The main source of fentanyl was diversion of medicines, notably transdermal patches. Fentanyl, butyrfentanyl and furanylfentanyl are administered orally, buccally, sublingually, intranasally, by inhalation and intravenously. Concomitant use of fentanyl and its derivatives with other psychoactive compounds increases the risk of severe adverse effects. CONCLUSIONS: Our study contributed to amore comprehensive understanding of problems related to abuse of fentanyl, butyrfentanyl and furanylfentanyl in Poland. In the light of the relatively high popularity of pharmaceutical fentanyl used for non-medical purposes, there is an urgent need for more strict control over illegal sales of fentanyl transdermal preparations via the Internet, as well as disposal of used patches. Furthermore, patients using fentanyl should be warned that giving it to another person is against the law, and may lead to development of addiction and other serious health consequences. It is important to educate the society in order to increase awareness of the problem of opioid use, especially by young people, and to pay attention to signals which may indicate addiction among family members.

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.

[Health consequences of shift work]. / Skutki zdrowotne pracy zmianowej.

In humans many biochemical, physiological and behavioral processes occur in a rhythmic manner. Accumulating experimental and epidemiological evidence indicate that disturbances in biological rhythms could lead to unfavorable alterations in body function, thus exerting negative health impact. In industrialized countries, it is estimated that between 15 and 30% of the working population is involved in some kind of permanent night work and rotating shift work. Today, shift work is regarded as a significant occupational stressor which has marked negative effects on both health and well-being. This review surveys data on association between shift work and health problems, including sleep disorders, cardiovascular disease, peptic ulcer, metabolic syndrome, breast cancer and undesirable pregnancy outcome.

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.

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.

[Nighttime eating disorders--clinical symptoms and treatment]. / Nocne zaburzenia jedzenia--obraz kliniczny i leczenie.

Nighttime eating is categorized as either night eating syndrome (NES) or the sleep-related eating disorder (SRED). Both diseases are often connected with an increase of the body mass, obesity, and with psychiatric disturbances. NES is characterized by evening hyperphagia, abnormally increased food intake after the evening meal, nocturnal awakings with ingestions, morning anorexia, and insomnia. Patients suffering from NES are aware of their nocturnal ingestions. It is suggested that NES is an abnormality in the circadian rhythm of meal timing that occurs in people with normal circadian rhythm of sleep. Other factors underlying NES include genetic predispositions, hormonal and neurochemical disturbances, and mood disorders. SRED is characterized by recurrent episodes of eating or drinking after arousal from nighttime sleep, unaware in tight the most cases, with adverse consequences. The distinctive features of SRED are amnesia of night eating episodes and consumption of non-typical food or dangerous articles. SRED is frequently associated with other sleep disorders, e.g., restless leg syndrome, periodic limb movement disorder, obstructive sleep apnea, and somnambulism. It can be also induced by medicines applied by a patient (e.g. zolpidem). It is hypothesized that the syndrome represents a variation of somnambulism. In the treatment of NES both non-pharmacological methods (psychotherapy, phototherapy) as well as the pharmacotherapy (aimed to increase serotoninergic neurotransmission in the brain, predominantly by sertraline, a selective serotonin re-uptake inhibitor) are used. SRED can be treated by controlling comorbid sleep disorders and eliminating provocative sedative hypnotics.

NBOMes-Highly Potent and Toxic Alternatives of LSD.

Recently, a new class of psychedelic compounds named NBOMe (or 25X-NBOMe) has appeared on the illegal drug market. NBOMes are analogs of the 2C family of phenethylamine drugs, originally synthesized by Alexander Shulgin, that contain a N-(2-methoxy)benzyl substituent. The most frequently reported drugs from this group are 25I-NBOMe, 25B-NBOMe, and 25C-NBOMe. NBOMe compounds are ultrapotent and highly efficacious agonists of serotonin 5-HT2A and 5-HT2C receptors (Ki values in low nanomolar range) with more than 1000-fold selectivity for 5-HT2A compared with 5-HT1A. They display higher affinity for 5-HT2A receptors than their 2C counterparts and have markedly lower affinity, potency, and efficacy at the 5-HT2B receptor compared to 5-HT2A or 5-HT2C. The drugs are sold as blotter papers, or in powder, liquid, or tablet form, and they are administered sublingually/buccally, intravenously, via nasal insufflations, or by smoking. Since their introduction in the early 2010s, numerous reports have been published on clinical intoxications and fatalities resulting from the consumption of NBOMe compounds. Commonly observed adverse effects include visual and auditory hallucinations, confusion, anxiety, panic and fear, agitation, uncontrollable violent behavior, seizures, excited delirium, and sympathomimetic signs such mydriasis, tachycardia, hypertension, hyperthermia, and diaphoresis. Rhabdomyolysis, disseminated intravascular coagulation, hypoglycemia, metabolic acidosis, and multiorgan failure were also reported. This survey provides an updated overview of the pharmacological properties, pattern of use, metabolism, and desired effects associated with NBOMe use. Special emphasis is given to cases of non-fatal and lethal intoxication involving these compounds. As the analysis of NBOMes in biological materials can be challenging even for laboratories applying modern sensitive techniques, this paper also presents the analytical methods most commonly used for detection and identification of NBOMes and their metabolites.

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.

Dopamine in the Turkey retina-an impact of environmental light, circadian clock, and melatonin.

Substantial evidence suggests that dopamine and melatonin are mutually inhibitory factors that act in the retina as chemical analogs of day and night. Here, we show an impact of environmental light, biological clock, and melatonin on retinal levels of dopamine and its major metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the turkey. In turkeys held under different light (L) to dark (D) cycles (16L:8D, 12L:12D, 8L:16D), retinal levels of dopamine and DOPAC fluctuated with daily rhythms. High levels of dopamine and DOPAC were observed during light hours and low during dark hours. Under the three photoperiodic regimes, rhythms of dopamine and DOPAC were out of phase with daily oscillation in retinal melatonin content. In constant darkness, dopamine and DOPAC levels oscillated in circadian rhythms. Light deprivation resulted, however, in a significant decline in amplitudes of both rhythms. Injections of melatonin (0.1-1 mumol/eye) during daytime significantly reduced retinal levels of DOPAC. This suppressive effect of melatonin was more pronounced in the dark-adapted than light-exposed turkeys. Quinpirole (a D(2)/D(4)-dopamine receptor agonist; 0.1-10 nmol/eye) injected to dark-adapted turkeys significantly decreased retinal melatonin. Our results indicate that in the turkey retina: (1) environmental light is the major factor regulating dopamine synthesis and metabolism; (2) dopaminergic neurones are controlled, in part, by intrinsic circadian clock; and (3) dopamine and melatonin are components of the mutually inhibitory loop.

Physiology and pharmacology of melatonin in relation to biological rhythms.

Melatonin is an evolutionarily conserved molecule that serves a time-keeping function in various species. In vertebrates, melatonin is produced predominantly by the pineal gland with a marked circadian rhythm that is governed by the central circadian pacemaker (biological clock) in the suprachiasmatic nuclei of the hypothalamus. High levels of melatonin are normally found at night, and low levels are seen during daylight hours. As a consequence, melatonin has been called the "darkness hormone". This review surveys the current state of knowledge regarding the regulation of melatonin synthesis, receptor expression, and function. In particular, it addresses the physiological, pathological, and therapeutic aspects of melatonin in humans, with an emphasis on biological rhythms.

An expanding world of new psychoactive substances-designer benzodiazepines.

The abuse of new psychoactive substances (NPS) has been increasing dramatically since the late 2000s worldwide. Between 2009 and 2017, a total of 803 individual NPS were reported to the United Nations Office of Drugs and Crime by 111 countries and territories. Although the most popular compounds are synthetic cannabinomimetics and psychostimulatory derivatives of cathinone (so-called ß-keto-amphetamines), novel benzodiazepines have recently emerged on the recreational drug market. The misuse/abuse of "designer benzodiazepines" (DBZD), a common name for the benzodiazepine class NPS, has become an increasing problem in many countries. The DBZD group includes pharmaceutical drug candidates that have never been approved for medical use, compounds that were synthesized by a simple structural modification of a registered drug, and some active metabolites of registered benzodiazepines. This survey presents members of the DBZD group, describes the epidemiological trends and clinical effects associated with DBZD use, and discusses available data on their metabolism. Special emphasis is given to cases of intoxications involving these compounds.

Induction of immediate early genes expression in the mouse striatum following acute administration of synthetic cathinones.

BACKGROUND: Synthetic cathinones (SCs) form one of the most prominent group of the New Psychoactive Substances. SCs enhance central dopaminergic and noradrenergic neurotransmission, and are used as substitutes for illicit psychostimulants, namely cocaine, amphetamine, and methamphetamine. Changes in the expression of immediate early genes (IEGs) in the striatum underlie the addictive potential of drugs of abuse belonging to distinct pharmacologic groups. This work was aimed to assess the impact of acute administration of the prominent SCs on the mRNA levels of IEGs in the mouse striatum. METHODS: Effects of 3,4-MDPV, 2,3-MDPV, α-PVP, PV8, PV9, methcathinone (MC) and 3-fluoromethcathinone (3-FMC) on the mRNA levels of ten IEGs, one and two hours after exposure, were measured in the mouse striatum using the quantitative RT-PCR technique. RESULTS: All SCs used in the study produced increased mRNA levels of the following IEGs: Areg, c-fos, Csrnp1, Dusp1, Dusp14, Egr2, Egr4 and FosB. Additionally, the majority of SCs increased the expression of Homer1 and c-jun. The magnitude of observed changes varied by the drug, analyzed gene and, in many cases, by time after administration. CONCLUSIONS: This study demonstrates that SCs increase the expression of IEGs in the mouse striatum, which may lead to a plethora of effects, as proteins encoded by the analyzed genes are involved in diverse actions, including an acute response to the drug and the neuroplasticity underlying the development of addiction.