Research in the Field of Drug Design and Development.

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.

Inhibitors of Endocannabinoids' Enzymatic Degradation as a Potential Target of the Memory Disturbances in an Acute N-Methyl-D-Aspartate (NMDA) Receptor Hypofunction Model of Schizophrenia in Mice.

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.

Magnoflorine from Berberis vulgaris Roots-Impact on Hippocampal Neurons in Mice after Short-Term Exposure.

In search of novel potential drug candidates that could be used as treatments or prophylactics for memory impairment, an aporphine alkaloid magnoflorine (MAG) isolated from the root of Berberis vulgaris was proven to exhibit beneficial anti-amnestic properties. Its effects on immunoreactivity to parvalbumin in the mouse hippocampus were assessed together with a study on its safety and concentration in the brain and plasma. For this purpose, four experimental groups were created: the MAG10 group-treated with 10 mg MAG/kg b.w. i.p., the MAG20 group-treated with 20 mg MAG/kg b.w. i.p., the MAG50 group-treated with 50 mg MAG/kg b.w. i.p., and a control group-injected with saline i.p. at a volume corresponding to their weight. Our results indicated that the hippocampal fields CA1-CA3 were characterized by an elevated number of parvalbumin-immunoreactive neurons (PV-IR) and nerve fibers in mice at the doses of 10 and 20 mg/kg b.w. (i.p.). No significant changes to the levels of IL-1ß, IL-6 or TNF-α were observed for the above two doses; however, the administration of 50 mg/kg b.w. i.p. caused a statistically significant elevation of IL-6, IL-1beta plasma levels and an insignificant raise in the TNF-alpha value. The HPLC-MS analysis showed that the alkaloid's content in the brain structures in the group treated with 50 mg/kg b.w. did not increase proportionally with the administered dose. The obtained results show that MAG is able to influence the immunoreactivity to PV-IR in hippocampal neurons and might act as a neuroprotective compound.

Promising Advances in Pharmacotherapy for Patients with Spinal Cord Injury-A Review of Studies Performed In Vivo with Modern Drugs.

Spinal cord injury (SCI) is a pathological neurological condition that leads to significant motor dysfunction. It is a condition that occurs as a result of tragic accidents, violent acts, or as a consequence of chronic diseases or degenerative changes. The current treatments for patients with SCI have moderate efficacy. They improve the quality of life of patients, but they are still doomed to long-term disability. In response to the modern directions of research on possible therapeutic methods that allow for the recovery of patients with SCI, a scientific review publication is needed to summarize the recent developments in this topic. The following review is focused on the available pharmacological treatments for SCIs and the problems that patients face depending on the location of the injury. In the following review, the research team describes problems related to spasticity and neuropathic pain; possible therapeutic pathways are also described for neuroprotection and the improvement of neurotransmission within the injured spinal cord, and the review focuses on issues related to oxidative stress.

The Influence of CB2-Receptor Ligands on the Memory-Related Responses in Connection with Cholinergic Pathways in Mice in the Passive Avoidance Test.

Background: Dysfunction of the cholinergic system is associated with the development of Alzheimer's disease (AD). One of the new possible strategies for the pharmacological modulation of memory-related problems typical of AD, is connected with the endocannabinoid system (ECS) and the cannabinoid (CB: CB1 and CB2) receptors. Methods: The aim of the study was to determine the influence of the selective CB2 receptor ligands: agonist (JWH 133) and antagonist (AM 630) on different stages of memory and learning in mice, in the context of their interaction with cholinergic pathways. To assess and understand the memory-related effects in mice we used the passive avoidance (PA) test. Results: We revealed that co-administration of non-effective dose of JWH 133 (0.25 mg) or AM 630 (0.25 mg/kg) with the non-effective dose of cholinergic receptor agonist - nicotine (0.05 mg/kg) enhanced cognition in the PA test in mice; however, an acute injection of JWH 133 (0.25 mg/kg) or AM 630 (0.25 mg/kg) had no influence on memory enhancement induced by the effective dose of nicotine (0.1 mg/kg). Co-administration of JWH 133 (0.25 mg) or AM 630 (0.25 mg/kg) with the effective dose of the cholinergic receptor antagonist scopolamine (1 mg/kg) attenuated the scopolamine-induced memory impairment in the PA test in mice. Conclusion: Our experiments have shown that CB2 receptors participate in the modulation of memory-related responses, especially those in which cholinergic pathways are implicated.

Cannabidiol Attenuates MK-801-Induced Cognitive Symptoms of Schizophrenia in the Passive Avoidance Test in Mice.

Schizophrenia is a chronic mental disorder that disturbs feelings and behavior. The symptoms of schizophrenia fall into three categories: positive, negative, and cognitive. Cognitive symptoms are characterized by memory loss or attentional deficits, and are especially difficult to treat. Thus, there is intense research into the development of new treatments for schizophrenia-related responses. One of the possible strategies is connected with cannabidiol (CBD), a cannabinoid compound. This research focuses on the role of CBD in different stages of memory (acquisition, consolidation, retrieval) connected with fear conditioning in the passive avoidance (PA) learning task in mice, as well as in the memory impairment typical of cognitive symptoms of schizophrenia. Memory impairment was provoked by an acute injection of the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (animal model of schizophrenia). Our results revealed that an acute injection of CBD (30 mg/kg; intraperitoneally (i.p.) improved all phases of long-term fear memory in the PA test in mice. Moreover, the acute injection of non-effective doses of CBD (1 or 5 mg/kg; i.p.) attenuated the memory impairment provoked by MK-801 (0.6 mg/kg; i.p.) in the consolidation and retrieval stages of fear memory, but not in the acquisition of memory. The present findings confirm that CBD has a positive influence on memory and learning processes in mice, and reveals that this cannabinoid compound is able to attenuate memory impairment connected with hypofunction of glutamate transmission in a murine model of schizophrenia.

Effect of Berberine Isolated from Barberry Species by Centrifugal Partition Chromatography on Memory and the Expression of Parvalbumin in the Mouse Hippocampus Proper.

Neurodegenerative diseases associated with memory disturbances are important health issues occurring due to a prolonged life span. This article presents the results of a study targeting the emergence of a drug candidate with antiamnesic properties. The effect of berberine (BBR), an isoquinoline alkaloid isolated from the overground parts of Berberis sibirica Pall., on memory and expression of parvalbumin in the mouse hippocampus proper were determined. High-purity BBR was isolated by centrifugal partition chromatography from a methanolic extract from B. sibirica by using a methyl-tert-butyl ether and water (1:1 v/v) solvent system with 10 mmol/L of triethylamine and hydrochloric acid. In an in vivo study, we assessed the influence of the chronic administration of BBR on different stages of memory-related responses in mice. Our results indicated that the chronic administration of BBR in a higher dose (5 mg/kg) improves long-term memory acquisition in mice, as determined in the passive avoidance test. The hippocampal CA1-CA3 fields showed an increased number of parvalbumin-immunoreactive neurons (PV-IR) and nerve fibers as compared to the control. No significant changes in the dentate gyrus were observed between the groups. The HPLC-ESI-QTOF-MS/MS analysis of the biological material revealed the content of BBR as 363.4 ± 15.0 ng (4.11% of RSD) per brain, 15.06 ± 0.89 ng (5.91% of RSD) per hippocampus, and 54.45 ± 1.40 (4.05% of RSD) ng in 100 µL plasma. The study showed that BBR could be a factor influencing the expression of PV in hippocampal neurons. We speculate that BBR may modulate the level of Ca2+ in neurons and thus potentially act as a neuroprotective factor against neuronal damages.

N-(3-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}propyl)-1H-indazole-3-carboxamide (D2AAK3) as a potential antipsychotic: In vitro, in silico and in vivo evaluation of a multi-target ligand.

Schizophrenia is a mental illness of not adequately understood causes that is not satisfactorily enough treated by current antipsychotics. In search for novel potential antipsychotics we performed structure-based virtual screening aimed to identify new dopamine D2 receptor antagonists. We found compound D2AAK3 with affinity to dopamine D2 receptor of 115 nM. D2AAK3 possesses additional nanomolar or low micromolar affinity to D1, D3, 5-HT1A, 5-HT2A and 5-HT7 receptors, which makes it a good hit for further development as a multifunctional ligand. The compound has also some affinity to M1 and H1 receptors. We used homology modeling, molecular docking and molecular dynamics to study interactions of D2AAK3 with its molecular targets at the molecular level. In behavioral studies D2AAK3 decreases amphetamine-induced hyperactivity (when compared to the amphetamine-treated group) measured as spontaneous locomotor activity in mice. In addition, passive avoidance test demonstrated that D2AAK3 improves memory consolidation after acute treatment in mice. Elevated plus maze tests indicated that D2AAK3 induces anxiogenic activity 30 min after acute treatment, whereas this effect has no longer been observed 60 min after administration of the studied compound in mice.

Bergapten Improves Scopolamine-Induced Memory Impairment in Mice via Cholinergic and Antioxidative Mechanisms.

Bergapten is a furanocoumarin naturally occurring in the Apiaceae family and it is a well-known photosensitizing agent used in photochemotherapy. In this study, we investigated the influence of bergapten on cognitive function and mechanism underlying these effects in scopolamine-induced memory impairment in male Swiss mice. The passive avoidance test was used to evaluate the efficiency of memory acquisition and consolidation. The results demonstrated that both single and repeated administration of bergapten improved not only the acquisition but also consolidation of memory. The behavioral tests showed that bergapten prevented memory impairment induced by administration of scopolamine. Observed effects may result from the inhibition of acetylcholinesterase activity in the hippocampus and prefrontal cortex. Also, bergapten caused significant anti-oxidative effects. These new findings provide pharmacological and biochemical support for the development of the coumarin's potential in cognitive deficits.

Contribution of CB2 receptors in schizophrenia-related symptoms in various animal models: Short review.

Schizophrenia is a severe and chronic mental disease with a high prevalence and a variety of symptoms. Data from behavioural studies suggest that it is rational to investigate the endocannabinoid system (ECS) and its cannabinoid receptor (CBr) because they seem to underlie susceptibility to schizophrenia, and these findings have pointed to several lines of future research. Currently, most available studies address the role of CBr type 1 in schizophrenia-like responses. Here, we present for the first time, a review that demonstrates the pivotal role of CBr type 2 in the regulation of neurobiological processes underlying cognition, psychosis- and mood-related (anxiety, depression) behaviours, all of which may be included in schizophrenia symptoms. This review is based on available evidence from the PubMed database regarding schizophrenia-like symptoms induced via CB2r modulation in various animal models. The data presented in this manuscript indicate that CB2r could be a promising new key target in the treatment of different central nervous system (CNS) disorders, which manifest as psychosis, mood-related disturbances and/or memory impairment.

Impact of the metabotropic glutamate receptor7 (mGlu7) allosteric agonist, AMN082, on fear learning and memory and anxiety-like behavior.

The present study was conducted to evaluate the influence of AMN082, the metabotropic glutamate receptor subtype 7 (mGlu7) allosteric agonist on different stages of memory processes connected with fear conditioning in the passive avoidance (PA) learning task in mice and negative emotional state (anxiety-like) induced by ethanol- and morphine-withdrawal in the elevated plus maze (EPM) test in rats. To perform the PA test, AMN082 (1.25, 2.5 and 5 mg/kg, i. p.) was injected to interfere with (or inhibit) acquisition, consolidation, and retrieval processes. The retention latency in each group was recorded using a step-through passive avoidance task 24 h after training. In turn, in ethanol- and morphine-withdrawal rats, the influence of AMN082 on anxiety-like behavior was estimated in the EPM test 24 h- (ethanol) and 72- h (morphine) after the last dose of repeated drug administrations. In all experimental groups, AMN082 at the dose of 5 mg/kg significantly decreased the step-through latency of long-term memory in the PA task. These AMN082 effects were reversed by MMPIP (10 mg/kg), the antagonist of mGlu7 receptor. AMN082 (2.5 and 5 mg/kg) also decreased ethanol- and morphine withdrawal-induced anxiety-like behavior in the EPM test, and this AMN082 (5 mg/kg) effect was counteracted by MMPIP pretreatment. Taken together, the results show that mGlu7 is involved in fear learning to the context and anxiety-like state connected with unpleasant experiences after ethanol- and morphine withdrawal in rodents. However, it appears that functional dissociation exists between these two AMN082 effects.

Effects of Fatty Acid Amide Hydrolase Inhibitors Acute Administration on the Positive and Cognitive Symptoms of Schizophrenia in Mice.

The connection between the endocannabinoid system (ECS) and schizophrenia is supported by a large body of research. The ECS is composed of two types cannabinoid (CB: CB1 and CB2) receptors and their endogenous ligands, endocannabinoids. The best-known endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), are intracellularly degraded by fatty acid hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. Thus, the function of ECS might be modulated in a direct way, through CB receptor ligands or indirectly by FAAH and MAGL inhibitors. We evaluated that the direct influence of ECS, using FAAH (URB 597) and MAGL (JZL 184) inhibitors, on the schizophrenia-like effects in mice. The behavioral schizophrenia-like symptoms were obtained in animals by using N-methyl D-aspartate (NMDA) receptor antagonists, MK-801. An acute administration of MK-801 (0.3 and 0.6 mg/kg) induced psychotic symptoms in rodents, manifested as the increase in locomotor activity, measured in actimeters, as well as the memory impairment, assessed in the passive avoidance (PA) task. We revealed that an acute administration of URB 597, at the dose of 0.3 mg/kg, attenuated MK-801 (0.6 mg/kg)-induced memory impairment. In turn, an acute administration of URB 597 at a higher dose (1 mg/kg) potentiated MK-801 (0.3 mg/kg)-induced memory impairment. Similarly, an acute administration of JZL 184 (20 and 40 mg/kg) intensified an amnestic effect of MK-801 (0.3 mg/kg). Moreover, an acute injection of JZL 184 (1 mg/kg) potentiated hyperlocomotion is provoked by MK-801 (0.3 and 0.6 mg/kg) administration. The present findings clearly indicate that ECS, through an indirect manner, modulates a variety of schizophrenia-like responses in mice.

Rutin as Neuroprotective Agent: From Bench to Bedside.

Flavonoids are major dietary constituents of plant-based food found ubiquitously in plant kingdom where they are usually present in substantial amounts. Rutin is a flavonol-type polyphenol which consists of the flavonol quercetin and the disaccharide rutinose. Rutin has been reported to exert diverse biological effects such as antitumor and antimicrobial mainly associated to its antioxidant and anti-inflammatory activities. Mental, neurological, and behavioural disorders are an important and growing cause of morbidity. Most of these disorders combine a high prevalence, early onset, progressive clinical course, and impairment of critical brain functions making them a major contributor to the global disease burden. In the present work, the biological in vitro and in vivo effects and the potential therapeutic applications of rutin in neurodegenerative processes are reviewed, as well as their bioavailability and pharmacokinetics, which are essential for a better understanding of its biological effectiveness. Moreover, the present review also provides an overview of the molecular mechanisms through which rutin is proposed to exert its neuroprotective effects.

Acute MDMA and Nicotine Co-administration: Behavioral Effects and Oxidative Stress Processes in Mice.

3,4-Methylenedioxy-methylamphetamine (MDMA), a synthetic substance commonly known as ecstasy, is a worldwide recreational drug of abuse. As MDMA and nicotine activate the same neuronal pathways, we examined the influence of co-administration of nicotine (0.05 mg/kg) and MDMA (1 mg/kg) on cognitive processes, nicotine-induced behavioral sensitization and on processes linked with oxidative stress and α7 nicotinic acetylcholine receptors (nAChRs) expression in the brain of male Swiss mice. For behavioral study the passive avoidance (PA) test and locomotor sensitization paradigm were used. Also, the oxidative stress parameters as well as expression levels of α7 nAChRs in prefrontal cortex and hippocampus of mice treated with MDMA alone or in combination with nicotine were assessed. The results revealed that MDMA injections as well as co-administrations of MDMA and nicotine improved memory consolidation in male Swiss mice tested in PA task. Furthermore, one of the main findings of the present study is that MDMA increased locomotor activity in nicotine-sensitized mice. Our study showed for the first time strong behavioral and biochemical interactions between nicotine and MDMA. Both drugs are very often used in combination, especially by young people, thus these results may help explaining why psychoactive substances are being co-abused and why this polydrug administration is still a social problem.

The role of verapamil and SL-327 in morphine- and ethanol-induced state-dependent and cross state-dependent memory.

Drugs of abuse trigger a very specific type of memory called state-dependent memory (SDM). Both memory process and drug addiction are underlain by neuroplasticity, which depends on calcium concentration and protein kinase activity. Within the scope of this study was to evaluate the impact of verapamil, an L-type voltage-gated calcium channel (VGCC) blocker, and SL-327, a selective MAPK/ERK kinase inhibitor, on morphine and ethanol SDM including the cross effects between these drugs with an additional influence of nicotine. To assess SDM in mice a step-through passive avoidance task was used. Our results show that amnestic effects of morphine (10.0 mg/kg, s.c.) and ethanol (1.0 g/kg, i.p.) can be reversed by pre-test administrations of morphine (10.0 mg/kg, s.c.), ethanol (1.0 g/kg, i.p.) and nicotine (0.1 mg/kg, s.c.), indicating morphine and ethanol SDM, as well as morphine-ethanol, morphine-nicotine, ethanol-morphine and ethanol-nicotine cross SDM. Pre-test co-treatment of verapamil (10.0 mg/kg, i.p.) with morphine/ethanol/nicotine increased all investigated SDM and cross SDM effects. Pre-test co-treatment of SL-327 (10.0 mg/kg, i.p.) diminished morphine- and ethanol-induced SDM along with the cross effects except ethanol-morphine cross SDM. In conclusion, SDM depends on ERK1/2 activation and also verapamil affects this type of memory, although the exact mechanism of its cognitive action has not been investigated in this study.

Impacts of cannabinoid receptor ligands on nicotine- and chronic mild stress-induced cognitive and depression-like effects in mice.

Taking into account the rather frequent concomitance of nicotine abuse and stress, we aimed to research memory- and depression-related effects of nicotine administration in combination with chronic mild unpredictable stress (CMUS) in mice and an involvement of the endocannabinoid system through CB1 and CB2 receptors. Mice were submitted to the CMUS for 4 weeks. Effects on depression-like behaviors and cognition, exerted by a combined administration of CB1, i.e., Oleamide (2.5, 5.0 mg/kg), AM 251 (0.1, 0.25 mg/kg) and CB2, i.e., JWH 133 (0.5, 2.0 mg/kg), AM 630 (0.25, 2.0 mg/kg) receptor ligands and nicotine (0.05, 0.1, 0.2 and 0.5 mg/kg), were then studied in stressed and unstressed mice by the forced swimming test and the passive avoidance paradigm, respectively. The results revealed that the CMUS-exposed mice exhibited depression-like behaviors and memory disturbances, while both effects were alleviated by nicotine. CB1 receptor ligands decreased antidepressive and cognitive (the latter for CB1 receptor antagonist only) effects of subchronic nicotine administration in stressed mice. CB1 and CB2 receptor antagonists exerted themselves some procognitive effects in those mice. Regarding the unstressed mice, CB1 and CB2 receptor ligands reversed the antidepressive effects of subchronic nicotine administration, while nicotine, in an ineffective dose, co-administered with CB2 receptor ligands, improved cognition. We confirmed the role of the two main subtypes of cannabinoid receptors, termed CB1 and CB2, on stress- and nicotine-related behavioral changes in mice. Our study has contributed to the understanding of the mechanisms involved in stress- and nicotine-induced disorders, such as anhedonia and memory disturbances.

The Evaluation of Pro-Cognitive and Antiamnestic Properties of Berberine and Magnoflorine Isolated from Barberry Species by Centrifugal Partition Chromatography (CPC), in Relation to QSAR Modelling.

Civilization diseases associated with memory disorders are important health problems occurring due to a prolonged life span. The manuscript shows the results of an in vivo study targeting the emergence of two drug candidates with anti-amnestic properties. The preceding quantitative structure-activity relationship (QSAR) studies provided information on the ability of berberine and magnoflorine to cross the blood-brain barrier (BBB). In the light of these findings, both compounds were purified from crude plant extracts of barberries: berberine-from Berberis siberica using a method published earlier, and magnoflorine-from Berberis cretica by centrifugal partition chromatography (solvent system: ethyl acetate:butanol:water-0.6:1.5:3 v/v/v). Both the compounds were evaluated for their memory enhancing and scopolamine inhibitory properties in an in vivo passive avoidance (PA) test on mice towards short-term and long-term memory. Cognition enhancing properties were observed at the following doses: 5 mg/kg (i.p.) for berberine and 20 mg/kg (i.p.) for magnoflorine. In addition, both the tested isoquinolines with the co-administered scopolamine were found to block long-term but not short-term memory impairment. No influence on the locomotor activity was observed for the tested doses. The results confirmed a marked central activity of magnoflorine and showed the necessity to lower the dosage of berberine. Optimized purification conditions have been elaborated for magnoflorine.

The Impact of CB2 Receptor Ligands on the MK-801-Induced Hyperactivity in Mice.

It has been known that there is a relationship between cannabis use and schizophrenia-related symptoms; however, it can be a subject of controversy. The involvement of CB1 receptor ligands in the schizophrenia has already been revealed and confirmed. However, there is still lack of information concerning the role of CB2 receptors in the psychosis-like effects in mice and the further studies are needed.The aim of the present research was to study the role of the CB2 receptor ligands in the symptoms typical for schizophrenia. We provoked hyperlocomotion in mice which is analogous to positive psychosis-like effects in humans, by an acute administration of a NMDA receptor antagonist, MK-801 (0.3 and 0.6 mg/kg), a pharmacological model of schizophrenia. An acute administration of MK-801 induced the increase in locomotor activity (hyperactivity) in rodents, measured in actimeters.We revealed that an acute injection of CB2 receptor agonist JWH 133 at the dose range (0.05-1.0 mg/kg) and CB2 receptor antagonist, AM 630 at the dose range (0.1-1.0 mg/kg) decreased locomotion of mice. An acute injection of JWH 133 (2.0 mg/kg) and AM 630 (2.0 mg/kg) had no statistical significant influence on the locomotor activity of mice. However, an acute injection of both CB2 receptor ligands (agonist and antagonist), JWH 133, at the non-effective dose of 2.0 mg/kg and AM 630 at the non-effective dose of 2.0 mg/kg, potentiated the MK-801-induced hyperactivity.The present findings have confirmed that endocannabinoid system, not only via CB1, but also via CB2 receptors, may be involved in the schizophrenia-like responses, including hyperlocomotion in mice.

Endocannabinoid System: the Direct and Indirect Involvement in the Memory and Learning Processes-a Short Review.

The endocannabinoid system via cannabinoid (CB: CB1 and CB2) receptors and their endogenous ligands is directly and indirectly involved in many physiological functions, especially in memory and learning processes. Extensive studies reported that this system strictly modulates cognition-related processes evaluated in various animal models. However, the effects of cannabinoids on the cognition have been contradictory. The cannabinoid compounds were able to both impair or improve different phases of memory processes through direct (receptor related) or indirect (non-receptor related) mechanism. The memory-related effects induced by the cannabinoids can be depended on the kind of cannabinoid compound used, dosage, and route of administration as well as on the memory task chosen. Therefore, the objectives of this paper are to review and summarize the results describing the role of endocannabinoid system in cognition, including various stages of memory.

The Influence of the CB1 Receptor Ligands on the Schizophrenia-Like Effects in Mice Induced by MK-801.

A growing body of psychiatric research has emerged, focusing on the role of endocannabinoid system in psychiatric disorders. For example, the endocannabinoid system, via cannabinoid CB (CB1 and CB2) receptors, is able to control the function of many receptors, such as N-methyl-D-aspartate (NMDA) receptors connected strictly with psychosis or other schizophrenia-associated symptoms. The aim of the present research was to investigate the impact of the CB1 receptor ligands on the symptoms typical for schizophrenia. We provoked psychosis-like effects in mice by an acute administration of NMDA receptor antagonist, MK-801 (0.1-0.6 mg/kg). An acute administration of MK-801 induced psychotic symptoms, manifested in the increase in locomotor activity (hyperactivity), measured in actimeters, as well as the memory impairment, assessed in the passive avoidance task. We revealed that an acute injection of CB1 receptor agonist, oleamide (5-20 mg/kg), had no influence on the short- and long-term memory-related disturbances, as well as on the hyperlocomotion in mice, provoking by an acute MK-801. In turn, an amnestic effects or hyperactivity induced by an acute MK-801 was attenuated by an acute administration of AM 251 (0.25-3 mg/kg), a CB1 receptor antagonist. The present findings confirm that endocannabinoid system is able to modify a variety of schizophrenia-like responses, including the cognitive disturbances and hyperlocomotion in mice. Antipsychotic-like effects induced by CB1 receptor antagonist, obtained in our research, confirm the potential effect of CB1 receptor blockade and could have important therapeutic implications on clinical settings, in the future.