Potential ability of cannabinoids to produce dependence is still a controversial issue. In our study, in order to examine the cannabinoid physical dependence phenomenon we administered CB1 receptor agonist WIN55,212-2, afterwards, in order to precipitate the withdrawal signs, chronically WIN 55,212-2 treated mice received an injection of rimonabant – an antagonist of CB1 receptors. The present study does not show that administration of rimonabant in mice chronically treated with the WIN 55,212-2 precipitated a signs of withdrawal syndrome.

Currently, no effective pharmacotherapy for psychostimulant abuse has indicated efficacy for long-term use. A better understanding of the neuropharmacological effects of cocaine and related psychostimulants has supported efforts to develop and improve useful medications for psychostimulant abuse and dependence. Functional agonist treatments may be used effectively to stabilize neurochemistry, influence behaviour and lead to long-term abstinence. Similarly, medications that target glutamatergic and GABAergic function are reasonable candidates that have received significant attention, and some have demonstrated effectiveness in reducing cocaine use and enhancing cocaine abstinence. However, these encouraging results will require additional clinical studies in order to identify safe and efficacious pharmacotherapies. Pharmacological mechanisms that may underline stimulants dependence were presented in this article. Furthermore, advances in pharmacotherapy were discussed.

In the present study, we investigated the mechanisms of cross-reinstatement of nicotine-induced place conditioning in rats. We used the conditioned place preference (CPP) paradigm and our data revealed that nicotine (0.175 mg/kg, base, i.p.) produced a place preference and once established, nicotine CPP was extinguished. Moreover the CB1 receptor agonist – WIN 55,212-2 (0.5 mg/kg, i.p.) or ethanol (0.5 g/kg, i.p.) reinstated a marked preference. Furthermore, we evaluated and compared the efficacy of the atypical antidepressant drug - bupropion (5, 10 and 20 mg/kg, i.p.) and a nonselective nicotinic receptor antagonist - mecamylamine (1 and 2 mg/kg, s.c.), in blocking the reinstatement of nicotine CPP provoked by WIN 55,212-2 and ethanol. Our results demonstrated that mecamylamine in all used doses and bupropion (except for dose of 10 mg/kg used in reinstatement induced by WIN 55,212-2) attenuated the reinstatement of nicotine-conditioned response induced by both drugs. Results obtained in the present studies may contribute to better understanding of the neurochemical mechanisms underlying nicotine addiction and the reciprocal relationships between nicotine, cannabis and ethanol.

Background: The endocannabinoid system (ECS) is one of the most important systems modulating functions in the body. The ECS, via cannabinoid (CB: CB1 and CB2) receptors, endocannabinoids occurring in the brain (e.g., anandamide (AEA) and 2-arachidonoylglycerol (2-AG)) and enzymes degrading endocannabinoids in the brain (fatty-acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL)), plays a key role in the regulation of mood and anxiety. However, the effects of cannabinoid compounds on anxiety-related responses are complex and yield mixed results depending on the type of pharmacological manipulation (direct or indirect) of functions of the ECS, as well as the kinds of cannabinoids, dosage and procedure. Methods: The aim of this study was to determine and compare the influence of the direct (via CB receptors ligands) and indirect (via inhibition of enzymes degrading endocannabinoids in the brain) pharmacological modulation of ECS function on anxiety-like responses in mice in the elevated plus maze (EPM) test. For this purpose, in the first step of the experiments, we used selected ligands of CB1, CB1/CB2 and CB2 receptors to assess which types of CB receptors are involved in anxiety-related responses in mice. Next, we used inhibitors of FAAH (which breaks down AEA) or MAGL (which breaks down 2-AG) to assess which endocannabinoid is more responsible for anxiety-related behavior in mice. Results: The results of our presented research showed that an acute administration of CB1 receptor agonist oleamide (5–20 mg/kg) had no influence on anxiety-related responses and CB1 receptor antagonist AM 251 (0.25–3 mg/kg) had anxiogenic effects in the EPM test in mice. In turn, an acute administration of mixed CB1/CB2 receptor agonist WIN55,212-2 used at a dose of 1 mg/kg had an anxiolytic effect observed in mice in the EPM test. What is of interest is that both the acute administration of a CB2 receptor agonist (JWH 133 at the doses of 1 and 2 mg/kg) and antagonist (AM 630 at the doses of 0.5–2 mg/kg) had anxiogenic effects in this procedure. Moreover, we revealed that an acute administration of only FAAH inhibitor URB 597 (0.3 mg/kg) had an anxiolytic effect, while MAGL inhibitor JZL 184 (at any used doses (2–40 mg/kg)) after an acute injection had no influence on anxiety behavior in mice, as observed in the EPM test. Conclusions: In our experiments, we confirmed the clearly significant involvement of the ECS in anxiety-related responses. In particular, the pharmacological indirect manipulation of ECS functions is able to elicit promising anxiolytic effects. Therefore, the ECS could be a potential target for novel anxiolytic drugs; however, further studies are needed.

Despite their effectiveness as analgesics, antitussives, antispasmodics and constipation drugs, opioids possess many side effects. Moreover, their easy availability contributes to the problem of addiction. In the following review, we focused on the toxicity and side effects of the four most common opioids – morphine, Codeine, Noscapine and Papaverine – to provide reliable information for students, doctors and pharmacists. Their pharmacological effects, as well as side effects have been described. Słowa kluczowe: opioids, toxicity, codeine, morphine, noscapine, papaverine

Current treatments for alcohol use disorder have limited efficacy underscoring the need for novel therapeutic targets. Trace amine-associated receptor 1 (TAAR1) is a promising candidate due to its ability to act as a brake on dopaminergic transmission and alcohol consumption. However, both the relative efficacy of full and partial TAAR1 agonists in reducing alcohol-related behaviors and their underlying mechanisms of action remain unclear. In this study, we evaluated the effects of the full agonist RO5166017 and the partial agonist RO5263397 on alcohol consumption using an intermittent access protocol in alcohol-preferring male C57BL/6JRj mice. Given their distinct pharmacological and electrophysiological properties, we also investigated the effects of these agonists on presynaptic dopaminergic transmission using fast-scan cyclic voltammetry in the nucleus accumbens, a key structure involved in alcohol reinforcement. Full and partial TAAR1 agonists reduced alcohol intake by 25 % and 43 %, respectively. We further report that these agonists exhibit opposite effects on dopamine release under basal conditions, but that these effects are reversed in animals chronically exposed to alcohol. The reversal in dopamine release did not result from alcohol-induced modifications of TAAR1 or D2 receptor expression. Our findings highlight the therapeutic potential of TAAR1 agonists for alcohol addiction and reveal important functional differences between full and partial agonists. Further research is needed to determine the clinical relevance of these distinct pharmacodynamic profiles and optimize TAAR1-targeting pharmacotherapies.

Alzheimer’s disease (AD) is one of the most common chronic neurodegenerative disorders worldwide. It is characterized by progressive memory loss and cognitive decline, leading to dementia. The pathogenesis of the disease is primarily attributed to two pathological protein structures: amyloid-beta (Aβ) plaques and tau protein neurofibrils. The current treatment strategies for AD are mainly symptomatic, highlighting the urgent need for the development of new, more effective therapies for the disease. The purpose of this paper is to provide a comprehensive and scientific review of the latest research regarding novel therapeutic options in the treatment of AD. In recent years, research has focused on more advanced and diversified strategies, including immunotherapy, gene therapy, tyrosine kinase inhibitors, therapies targeting mitochondrial function, and neurogenesis-related process modulation. One of the most promising treatment strategies for AD is immunotherapy. Intensive research is currently underway on both passive immunization, which involves the administration of monoclonal antibodies, and active immunization through vaccinations that stimulate the body to produce specific antibodies. Further research into novel therapeutic directions is essential, particularly concerning the role of the immune system in the pathogenesis of AD. Immunization appears to be a highly promising approach to developing effective methods for preventing AD or delaying the progression of this disease.

The synthesis of a new series of long-chain arylpiperazine as serotoninergic ligands (FG 1-18) is described. The combination of structural elements including heterocyclic nucleus, propyl chain, and 4,5-dihydrothiazol-2-ylphenylpiperazines leads to the preparation of different derivatives tested for their affinity toward 5-HT1A, 5-HT2A, and 5-HT2C receptors. The compounds with better affinity and selectivity binding profiles toward 5-HT1A and 5-HT2C (FG-1, FG-4, FG-5, FG-6, FG-7, FG-8, and FG-18) are selected for further in vivo assays to determine their functional activity. Finally, to rationalize the obtained results, molecular docking studies are performed. The results of pharmacological studies show that compounds FG-1, FG-5, FG-8, and FG-6 exert antidepressant-like effects, and FG-1, FG-18, FG-6, and FG-7 reveal also significant anxiolytic properties. Among the developed derivatives, the most promising compounds seem to be FG-1, which exhibit antidepressant, anxiolytic, and anticonvulsant properties, FG-7 and FG-18 that show features as anxiolytic combine to a pro-cognitive property and notable affinity and selectivity for 5-HT2C receptor, respectively.

Umbelliferone (7-hydroxycoumarin) is a naturally occurring coumarin with reported neuroprotective and anti-inflammatory actions, yet its integrated behavioral profile relevant to cognitive dysfunction and common neuropsychiatric comorbidities has remained insufficiently characterized. In this study, the effects of umbelliferone were evaluated in male Swiss mice following acute (5-50 mg/ kg, i.p.) and subchronic administration (twice daily), with afocus on learning and memory, anxiety-and depression-like behaviors, and potential confounding motor effects. Memory was assessed using the passive avoidance paradigm, including procedures probing both acquisition and consolidation, and an amnestic challenge was induced with scopolamine (1 mg/kg, i.p.); rivastigmine served as a reference procognitive compound. Umbelliferone improved passive avoidance performance, with the most consistent procognitive effects observed at 12.5-25 mg/kg and a stronger overall impact after subchronic dosing. In the scopolamine model, subchronic umbelliferone enhanced baseline performance and attenuated scopolamine-related impairment predominantly in the consolidation condition, whereas acquisition deficits were less consistently rescued. In contrast, umbelliferone produced anxiogenic-like effects in the elevated plus maze (reduced open-arm exploration) and showed no antidepressant-like activity in the forced swim test; repeated dosing increased immobility. Importantly, motor coordination (rotarod) and general locomotor activity were not impaired. Overall, umbelliferone displayed a robust procognitive profile without motor suppression, while highlighting an affective liability that should be considered in further translational development.

Background: Endocannabinoid system (ECS) via cannabinoid (CB: CB1 and CB2) receptors and enzymes degrading endocannabinoids in the brain (atty-acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), plays a key role in regulation of mood and anxiety. However, the effects of cannabinoid compounds on anxiety-related responses is complex and yield mixed results depending on the type of pharmacological manipulation (direct or indirect) of functions of ECS, as well as kind of cannabinoids, dosage and procedure. Methods: The aim of the study was to determine and compare the influence of the direct (via CB receptors ligands) and indirect (via inhibition of enzymes degrading endocannabinoids in the brain) pharmacological modulation of ECS function on the anxiety-like responses in mice in the elevated plus maze (EPM) test. For this purpose, in the first step of experiments we used selected ligands of CB1, CB1/CB2 and CB2 receptors to asses which type of CB receptors is involved in the anxiety-related responses in mice. Next, we used inhibitors of FAAH or MAGL to assess which enzyme is more responsible for anxiety-related behavior in mice. Results: The results of our presented research showed that an acute administration of CB1 receptor agonist – oleamide (5-20 mg/kg) had no influence on anxiety-related responses and CB1 receptor antagonist – AM 251 had anxiogenic (0.25-3 mg/kg) effects in the EPM test in mice. In turn, an acute administration of CB1/CB2 receptor agonist - WIN55,212-2 used at a dose of 1 mg/kg, had an anxiolytic effect observed in mice in the EPM test. What is of interest, both acute administration of CB2 receptor agonist (JWH 133 at the doses of 1 and 2 mg/kg) and antagonist (AM 630 at the doses of 0.5-2 mg/kg) had anxiogenic effects in this procedure. Moreover, we revealed that an acute administration of only FAAH inhibitor - URB 597 (0.3 mg/kg) had anxiolytic effect, while MAGL inhibitor (JZL 184) after an acute injection had no influence on anxiety behavior in mice observed in the EPM. Conclusion: In our experiments we confirmed the significant involvement of the ECS in anxiety-related responses. Both pharmacological indirect and direct (mainly through the CB1 receptors) manipulation of ECS functions is able to elicit promising anxiolytic effects. Therefore, ECS could be a potential target for novel anxiolytic drugs; however the further studies are needed.

Memory is one of the most important abilities of our brain. The process of memory and learning is necessary for the proper existence of humans in the surrounding environment. However, sometimes there are unfavourable changes in the functioning of the brain and memory deficits occur, which may be associated with various diseases. Disturbances in the cholinergic system lead to abnormalities in memory functioning and are an essential part of clinical symptoms of many neurodegenerative diseases. However, their treatment is difficult and still unsatisfactory; thus, it is necessary to search for new drugs and their targets, being an alternative method of mono- or polypharmacotherapy. One of the possible strategies for the modulation of memory-related cognitive disorders is connected with the endocannabinoid system (ECS). The aim of the present study was to determine for the first time the effect of administration of natural cannabinoid compound (cannabidiol, CBD) and rivastigmine alone and in combination on the memory disorders connected with cholinergic dysfunctions in mice, provoked by using an antagonist of muscarinic cholinergic receptor—scopolamine. To assess and understand the memory-related effects in animals, we used the passive avoidance (PA) test, commonly used to examine the different stages of memory. An acute administration of CBD (1 mg/kg) or rivastigmine (0.5 mg/kg) significantly affected changes in scopolamine-induced disturbances in three different memory stages (acquisition, consolidation, and retrieval). Interestingly, co-administration of CBD (1 mg/kg) and rivastigmine (0.5 mg/kg) also attenuated memory impairment provoked by scopolamine (1 mg/kg) injection in the PA test in mice, but at a much greater extent than administered alone. The combination therapy of these two compounds, CBD and rivastigmine, appears to be more beneficial than substances administered alone in reducing scopolamine-induced cognitive impairment. This polytherapy seems to be favourable in the pharmacotherapy of various cognitive disorders, especially those in which cholinergic pathways are implicated.

Treating schizophrenia with the available pharmacotherapy is difficult. One possible strategy is focused on the modulation of the function of the endocannabinoid system (ECS). The ECS is comprised of cannabinoid (CB) receptors, endocannabinoids and enzymes responsible for the metabolism of endocannabinoids (fatty acid hydrolase (FAAH) and monoacylglycerol lipase (MAGL)). Here, the aim of the experiments was to evaluate the impact of inhibitors of endocannabinoids' enzymatic degradation in the brain: KML-29 (MAGL inhibitor), JZL-195 (MAGL/FAAH inhibitor) and PF-3845 (FAAH inhibitor), on the memory disturbances typical for schizophrenia in an acute N-methyl-D-aspartate (NMDA) receptor hypofunction animal model of schizophrenia (i.e., injection of MK-801, an NMDA receptor antagonist). The memory-like responses were assessed in the passive avoidance (PA) test. A single administration of KML-29 or PF-3845 had a positive effect on the memory processes, but an acute administration of JZL-195 impaired cognition in mice in the PA test. Additionally, the combined administration of a PA-ineffective dose of KML-29 (5 mg/kg) or PF-3845 (3 mg/kg) attenuated the MK-801-induced cognitive impairment (0.6 mg/kg). Our results suggest that the indirect regulation of endocannabinoids' concentration in the brain through the use of selected inhibitors may positively affect memory disorders, and thus increase the effectiveness of modern pharmacotherapy of schizophrenia.

Two polyphenols–hyperoside (HYP) and protocatechuic acid (PCA) were reported to exert antidepressant activity in rodents after acute treatment. Our previous study also showed that this activity might have been influenced by the monoaminergic system and the upregulation of the brain-derived neurotropic factor (BDNF) level. A very long-term pharmacological therapy is required for the treatment of a patient with depression. The repetitive use of antidepressants is recognized to impact the brain structures responsible for regulating both emotional and cognitive behaviors. Thus, we investigated the antidepressant, anxiolytic, and procognitive effects of HYP and PCA in mice after acute and prolonged treatment (14 days). Both polyphenols induced an anxiogenic-like effect after acute treatment, whereas an anxiolytic effect occurred after repetitive administration. PCA and HYP showed procognitive effects when they were administered acutely and chronically, but it seems that their influence on long-term memory was stronger than on short-term memory. In addition, the preset study showed that the dose of 7.5 mg/kg of PCA and HYP was effective in counteracting the effects of co-administered scopolamine in the long-term memory impairment model induced by scopolamine. Our experiments revealed the compounds have no affinity for 5-HT1A and 5-HT2A receptors, whereas a significant increase in serum serotonin level after prolonged administration of PCA and HYP at a dose of 3.75 mg/kg was observed. Thus, it supports the involvement of the serotonergic system in the polyphenol mechanisms. These findings led us to hypothesize that the polyphenols isolated from Impatiens glandulifera can hold promise in treating mental disorders with cognitive dysfunction. Consequently, extended studies are necessary to delve into their pharmacological profile.

Nowadays, stressful situations are an unavoidable element of everyday life. Stressors activate a number of complex mental and physiological reactions in the organism, thus affecting the state of health of an individual. Stress is the main risk factor in the development of mental disorders, such as depression and other disorders developing as a result of addiction. Studies indicate that women are twice as likely as men to develop anxiety, depression and therefore addiction, e.g., to nicotine. Even though the data presented is indicative of significant differences between the sexes in the prevalence of these disorders, the majority of preclinical animal models for investigating stress-induced disorders use predominantly male subjects. However, the recent data indicates that this type of studies has also been launched in female rodents. Therefore, conducting research on both sexes allows for a more accurate understanding and assessment of the impact of stress on stress-induced behavioral, peripheral and molecular changes in the body and brain. In this manuscript we have gathered the data from 41 years (from 1981–2022) on the influence of stress on the development of depression and nicotine addiction in both sexes.

Depression is one of the greatest current mental disorders. Depressive disorder may affect everyone and it causes difficulties in social functioning and may lead to death via suicide. Depression is a serious problem because number of its cases is increasing, especially after pandemic of COVID-19. The oldest and the most approved theory which explains mechanism of depression’s development is a monoamine hypothesis. Effectiveness of most antidepressant drugs based on this theory. It assumes that the typical symptoms of depression are results of changed concentration of monoamines or incorrect monoaminergic transmission. The aim of this article is to present drugs which have influence on level of biogenic amines and are used in treatment of depressive disorders. Some of those drugs are the first choice in cure of this disease. In spite of adverse effects and often delayed onset of action of pharmacotherapy, it is still the first line in treatment of depression.

The processes used by academic and industrial scientists to discover new drugs have recently experienced a true renaissance, with many new and exciting techniques being developed over the past 5–10 years alone. Drug design and discovery, and the search for new safe and well-tolerated compounds, as well as the ineffectiveness of existing therapies, and society’s insufficient knowledge concerning the prophylactics and pharmacotherapy of the most common diseases today, comprise a serious challenge. This can influence not only the quality of human life, but also the health of whole societies, which became evident during the COVID-19 pandemic. In general, the process of drug development consists of three main stages: drug discovery, preclinical development using cell-based and animal models/tests, clinical trials on humans and, finally, forward moving toward the step of obtaining regulatory approval, in order to market the potential drug. In this review, we will attempt to outline the first three most important consecutive phases in drug design and development, based on the experience of three cooperating and complementary academic centers of the Visegrád group; i.e., Medical University of Lublin, Poland, Masaryk University of Brno, Czech Republic, and Comenius University Bratislava, Slovak Republic.

Twenty-five years have passed since the discovery of the orexin system, during which time we have learned more and more about it. A number of studies have been conducted showing the role of the orexin system in insomnia, as well as its potential use in the treatment of obesity and depression. In this review, we present the role of the orexin system in the development of depressive illness and show the characteristics of seltorexant, a potential drug for the treatment of depression. This review describes the structure and synthesis of the compound as well as its pharmacodynamics and pharmacokinetics. Pre-clinical and clinical studies are also described, including side effects. There is evidence that the use of seltorexant is considered safe, with no clear or major clinically significant side effects, which makes it a promising candidate for the treatment of depression and anxiety disorders.

Schizophrenia and depression are heterogeneous disorders. The complex pathomechanism of the diseases imply that medication responses vary across patients. Many psychotropic drugs are available but achieving optimal therapeutic effect can be challenging. The evidence correlates well with clinical observations, suggesting that new atypical antipsychotic drugs are effective against negative and cognitive symptoms of schizophrenia, as well as against affective symptoms observed in depression. The purpose of this review presents the background and evidence for the use of the new second/third-generation antipsychotics (aripiprazole, cariprazine, lurasidone, asenapine, brexpiprazole, lumateperone, pimavanserin) in treatment of schizophrenia and depression. We have first provided a brief overview of the major neurobiological underpinnings of schizophrenia and depression. We then shortly discuss efficacy, safety and limitations of ongoing pharmacotherapy used in depression and schizophrenia. Mainly, we have focused this review on the therapeutic potential of new atypical antipsychotic drugs-currently existing-to be effective in psychotic, as well as in affective disorders.

Insomnia affects 4.4–4.8% of the world’s population, but because the effect of hypnotic drugs is limited and may cause harmful side-effects, scientists are turning their attention to developing drugs that act on the orexin system. Daridorexant, a selective dual-orexin receptor antagonist (DORA), has exhibited promising results in both animal and human studies. Its activity was evaluated based on the physiology-based pharmacodynamic and pharmacokinetic model. The use of daridorexant is considered safe, with no clinically significant side-effects including deprivation of next-morning residual effects. In this manuscript we conducted a comprehensive review of daridorexant including pharmacodynamics, animal and human research, pharmacokinetics and safety.

It is commonly pointed out that enteric microbiota have a significant impact on the behavioral and neurophysiological parameters relevant to brain-gut axis disorders. Accordingly, many data have demonstrated that probiotics can alter the central nervous system function via this gut-brain axis and commensal bacteria consumption can ameliorate stress-related neuropsychiatric disorders. Thus, modulating the enteric microbiota is increasingly considered a new therapeutic approach for these disorders, although so far there is a lack of reliable pre-clinical and clinical data confirming the usefulness of probiotics in the treatment of affective disorders. In this review, we discuss various mechanisms linking specific probiotic bacteria with behaviors related to anhedonia and the exact mechanisms of their action, including data provided by using animal models and tests. Finally, we point to potential clinical impact resulting from future studies investigating the gut-brain axis activity with respect to the efficacy of probiotic treatment of mental disorders.