CB1 Receptor Ligands Research Articles

Morus alba, a Medicinal Plant for Appetite Suppression and Weight Loss.

The prevalence of obesity is expanding rapidly worldwide, making the disease a global burden with limited treatment options. The current obesity drug development trends suggest the possibility of reducing weight and reverse metabolic disturbances of obesity by controlling appetite. In this study, we screened more than 8000 plants from our plant library for the cannabinoid (CB1) receptor antagonists and identified Morus alba as a lead medicinal plant. Kuwanon G and Albanin G were isolated and identified from root-barks of Morus alba with 92% and 96% CB1 receptor ligand binding inhibitory activity, respectively. The bioflavonoid standardized extract was tested in the acute food intake study in rats at oral doses of 250 and 500 mg/kg for its appetite suppression activity. Diet-induced obesity in the C57BL/6J mice was used to evaluate the long-term food intake reduction activity and effect on the weight loss administered orally at 250 and 500 mg/kg for 7 weeks. Statistically significant and dose-dependent reduction in food intake was observed in both acute and long-term studies for the extract. Food intake reductions of 58.6% and 44.8% at 250 mg/kg and 50.1% and 44.3% at 500 mg/kg were observed at 1 and 2 h postfood provision, respectively. A 20% reduction in daily calorie intake was observed in the long-term study. Obese mice treated with the high dose of Morus root-bark extract showed 10.4 g (22.5%) and 7.1 g (16.5%) loss in body weight compared with the vehicle-treated obese animals (at week 7) and baseline, respectively. Statistically significant reductions in biochemical markers and visceral fat deposit were also observed. These results demonstrated that Morus alba extracts enriched in Kuwanon G, and Albanin G could be used alone to control appetite, manage body weight, and improve metabolic syndromes.

Model-free and kinetic modelling approaches for characterising non-equilibrium pharmacological pathway activity: Internalisation of cannabinoid CB1 receptors.

Receptor internalisation is by nature kinetic. Application of a standard equilibrium dose response model to describe the properties of a ligand inducing internalisation, while commonly used, are therefore problematic. Here, we propose two quantitative approaches to address this issue-(a) a model-free method and (b) a kinetic modelling approach-and systematically evaluate the performance of these methods against traditional equilibrium methods to characterise the internalisation profiles of cannabinoid CB1 receptor agonists. Kinetic internalisation assays were conducted using a concentration series of six CB1 receptor ligands. Internalisation rate analysis and snapshot equilibrium analysis were performed. A model-free method was developed based on the mean residence time of internalisation. A kinetic internalisation model was developed under the quasi-steady state assumption. Rates of receptor internalisation depended on both agonist and concentration. Agonist potencies from snapshot equilibrium analysis increased with stimulation time, and there was no single time point at which internalisation profiles could infer agonist properties in a comparative manner. The model-free method yielded a time-invariant measure of potency/efficacy for internalisation. The kinetic model adequately described the internalisation of CB1 receptors over time and provided robust estimates of both potency and efficacy. Applying equilibrium analysis to a non-equilibrium pathway cannot provide a reliable estimate of agonist potency. Both the model-free and kinetic modelling approaches characterised the internalisation profiles of CB1 receptor agonists. The kinetic model provides additional advantages as a method to capture changes in receptor number during other functional assays.

Development of Oxygen-Bridged Pyrazole-Based Structures as Cannabinoid Receptor 1 Ligands.

In this work, the synthesis of the cannabinoid receptor 1 neutral antagonists 8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-4,5-dihydrobenzo-1H-6-oxa-cyclohepta[1,2-c]pyrazole-3-carboxamide 1a and its deaza N-cyclohexyl analogue 1b has led to a deepening of the structure-activity studies of this class of compounds. A series of novel 4,5-dihydrobenzo-oxa-cycloheptapyrazoles analogues of 1a,b, derivatives 1c–j, was synthesized, and their affinity towards cannabinoid receptors was determined. Representative terms were evaluated using in vitro tests and isolated organ assays. Among the derivatives, 1d and 1e resulted in the most potent CB1 receptor ligands (KiCB1 = 35 nM and 21.70 nM, respectively). Interestingly, both in vitro tests and isolated organ assays evidenced CB1 antagonist activity for the majority of the new compounds, excluding compound 1e, which showed a CB1 partial agonist behaviour. CB1 antagonist activity of 1b was further confirmed by a mouse gastrointestinal transit assay. Significant activity of the new CB1 antagonists towards food intake was showed by preliminary acute assays, evidencing the potentiality of these new derivatives in the treatment of obesity.

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.

Structural Insights into CB1 Receptor Biased Signaling.

The endocannabinoid system has emerged as a promising target for the treatment of numerous diseases, including cancer, neurodegenerative disorders, and metabolic syndromes. Thus far, two cannabinoid receptors, CB1 and CB2, have been discovered, which are found predominantly in the central nervous system (CB1) or the immune system (CB2), among other organs and tissues. CB1 receptor ligands have been shown to induce a complex pattern of intracellular effects. The binding of a ligand induces distinct conformational changes in the receptor, which will eventually translate into distinct intracellular signaling pathways through coupling to specific intracellular effector proteins. These proteins can mediate receptor desensitization, trafficking, or signaling. Ligand specificity and selectivity, complex cellular components, and the concomitant expression of other proteins (which either regulate the CB1 receptor or are regulated by the CB1 receptor) will affect the therapeutic outcome of its targeting. With an increased interest in G protein-coupled receptors (GPCR) research, in-depth studies using mutations, biological assays, and spectroscopic techniques (such as NMR, EPR, MS, FRET, and X-ray crystallography), as well as computational modelling, have begun to reveal a set of concerted structural features in Class A GPCRs which relate to signaling pathways and the mechanisms of ligand-induced activation, deactivation, or activity modulation. This review will focus on the structural features of the CB1 receptor, mutations known to bias its signaling, and reported studies of CB1 receptor ligands to control its specific signaling.

Fluorescent triazolyl spirooxazolidines: Synthesis and NMR stereochemical studies

Carbon-heteoratom chemistry is a method of choice for rapid construction of complex molecules. In the recent decade, its various applications flourished thanks to the click chemistry approach. Herein, we use a combination of C-X bond formation reactions to complete the synthesis of 1,2,3-triazolyl spirooxazolidines, bearing the fluorenylmethoxycarbonyl (fmoc) substituent. Thanks to the application of 2D-NMR spectroscopic methods and a multilevel computational approach, including a medicinal chemistry – inspired conformational search, PM7 semiempirical and DFT-based geometry optimization finalized with DFT-GIAO NMR shielding constant calculation, we were able to investigate the conformational space and assign cis/trans configuration in complex NMR spectra. For the obtained fmoc derivatives we recorded UV-VIS absorption and emission spectra. The obtained compounds contain pharmacophoric groups characteristic for endocannabinoid system modulators- CB1 receptor ligands or FAAH inhibitors.

Brain activity of anandamide: a rewarding bliss?

Anandamide is a lipid mediator that acts as an endogenous ligand of CB1 receptors. These receptors are also the primary molecular target responsible for the pharmacological effects of Δ9-tetrahydrocannabinol, the psychoactive ingredient in Cannabis sativa. Several studies demonstrate that anandamide exerts an overall modulatory effect on the brain reward circuitry. Several reports suggest its involvement in the addiction-producing actions of other abused drugs, and it can also act as a behavioral reinforcer in animal models of drug abuse. Importantly, all these effects of anandamide appear to be potentiated by pharmacological inhibition of its metabolic degradation. Enhanced brain levels of anandamide after treatment with inhibitors of fatty acid amide hydrolase, the main enzyme responsible for its degradation, seem to affect the rewarding and reinforcing actions of many drugs of abuse. In this review, we will provide an overview from a preclinical perspective of the current state of knowledge regarding the behavioral pharmacology of anandamide, with a particular emphasis on its motivational/reinforcing properties. We will also discuss how modulation of anandamide levels through inhibition of enzymatic metabolic pathways could provide a basis for developing new pharmaco-therapeutic tools for the treatment of substance use disorders.

Controlled-Deactivation CB1 Receptor Ligands as a Novel Strategy to Lower Intraocular Pressure.

Nearly half a century has passed since the demonstration that cannabis and its chief psychoactive component Δ9-THC lowers intraocular pressure (IOP). Elevated IOP remains the chief hallmark and therapeutic target for glaucoma, a condition that places millions at risk of blindness. It is likely that Δ9-THC exerts much of its IOP-lowering effects via the activation of CB1 cannabinoid receptors. However, the initial promise of CB1 as a target for treating glaucoma has not thus far translated into a credible therapeutic strategy. We have recently shown that blocking monoacylglycerol lipase (MAGL), an enzyme that breaks the endocannabinoid 2-arachidonoyl glycerol (2-AG), substantially lowers IOP. Another strategy is to develop cannabinoid CB1 receptor agonists that are optimized for topical application to the eye. Recently we have reported on a controlled-deactivation approach where the “soft” drug concept of enzymatic deactivation was combined with a “depot effect” that is commonly observed with Δ9-THC and other lipophilic cannabinoids. This approach allowed us to develop novel cannabinoids with a predictable duration of action and is particularly attractive for the design of CB1 activators for ophthalmic use with limited or no psychoactive effects. We have tested a novel class of compounds using a combination of electrophysiology in autaptic hippocampal neurons, a well-characterized model of endogenous cannabinoid signaling, and measurements of IOP in a mouse model. We now report that AM7410 is a reasonably potent and efficacious agonist at CB1 in neurons and that it substantially (30%) lowers IOP for as long as 5 h after a single topical treatment. This effect is absent in CB1 knockout mice. Our results indicate that the direct targeting of CB1 receptors with controlled-deactivation ligands is a viable approach to lower IOP in a murine model and merits further study in other model systems.

Stereospecific Nucleophilic Substitution with Arylboronic Acids as Nucleophiles in the Presence of a CONH Group

AbstractStereospecific nucleophilic substitution was achieved for the first time with arylboronic acids as nucleophiles. This transition‐metal‐free coupling between chiral α‐aryl‐α‐mesylated acetamides and arylboronic acids provided access to a series of chiral α,α‐diaryl acetamides with excellent enantioselectivity and moderate to good yields. The CONH functionality proved to be crucial for bridging the reactants and promoting the reaction. Efficient syntheses of a cannabinoid CB1 receptor ligand, the antidepressant (S)‐diclofensine, and a key chiral building block of the inhibitor implitapide were successfully accomplished by using this method.

Stereospecific Nucleophilic Substitution with Arylboronic Acids as Nucleophiles in the Presence of a CONH Group.

Stereospecific nucleophilic substitution was achieved for the first time with arylboronic acids as nucleophiles. This transition-metal-free coupling between chiral α-aryl-α-mesylated acetamides and arylboronic acids provided access to a series of chiral α,α-diaryl acetamides with excellent enantioselectivity and moderate to good yields. The CONH functionality proved to be crucial for bridging the reactants and promoting the reaction. Efficient syntheses of a cannabinoid CB1 receptor ligand, the antidepressant (S)-diclofensine, and a key chiral building block of the inhibitor implitapide were successfully accomplished by using this method.

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.

Selective Photoaffinity Probe That Enables Assessment of Cannabinoid CB2 Receptor Expression and Ligand Engagement in Human Cells.

Chemical tools and methods that report on G protein-coupled receptor (GPCR) expression levels and receptor occupancy by small molecules are highly desirable. We report the development of LEI121 as a photoreactive probe to study the type 2 cannabinoid receptor (CB2R), a promising GPCR to treat tissue injury and inflammatory diseases. LEI121 is the first CB2R-selective bifunctional probe that covalently captures CB2R upon photoactivation. An incorporated alkyne serves as ligation handle for the introduction of reporter groups. LEI121 enables target engagement studies and visualization of endogenously expressed CB2R in HL-60 as well as primary human immune cells using flow cytometry. Our findings show that strategically functionalized probes allow monitoring of endogenous GPCR expression and engagement in human cells using tandem photoclick chemistry and hold promise as biomarkers in translational drug discovery.

Novel sulfenamides and sulfonamides based on pyridazinone and pyridazine scaffolds as CB1 receptor ligand antagonists

A series of sulfenamide and sulfonamide derivatives was synthesized and evaluated for the affinity at CB1 and CB2 receptors. The N-bornyl-S-(5,6-di-p-tolylpyridazin-3-yl)-sulfenamide, compound 11, displayed good affinity and high selectivity for CB1 receptors (Ki values of 44.6 nM for CB1 receptors and >40 μM for CB2 receptors, respectively). The N-isopinocampheyl-sulfenamide 12 and its sulfonamide analogue 22 showed similar selectivity for CB1 receptors with Ki values of 75.5 and 73.2 nM, respectively. These novel compounds behave as antagonists/inverse agonists at CB1 receptor in the [35S]-GTPγS binding assays, and none showed adequate predictive blood–brain barrier permeation, exhibiting low estimated LD50. However, testing compound 12 in a supraspinal analgesic test (hot-plate) revealed that it was as effective as the classic CB1 receptor antagonist rimonabant, in reversing the analgesic effect of a cannabinoid agonist.

Effects of arachidonyl-2'-chloroethylamide (ACEA) on the protective action of various antiepileptic drugs in the 6-Hz corneal stimulation model in mice.

Accumulating evidence indicates that cannabinoid CB1 receptor ligands play a pivotal role in seizures, not only in preclinical studies on animals, but also in clinical settings. This study was aimed at characterizing the influence of arachidonyl-2′-chloroethylamide (ACEA–a selective cannabinoid CB1 receptor agonist) co-administered with phenylmethylsulfonyl fluoride (PMSF) on the anticonvulsant potency of various antiepileptic drugs (clobazam, lacosamide, levetiracetam, phenobarbital, tiagabine and valproate) in the 6-Hz corneal stimulation model. Psychomotor seizures in male albino Swiss mice were evoked by a current (32 mA, 6 Hz, 3 s stimulus duration) delivered via corneal electrodes. Potential adverse effects produced by the antiepileptic drugs in combination with ACEA+PMSF were assessed using the chimney test (motor performance), passive avoidance task (remembering and acquisition of learning), and grip-strength test (muscular strength). Brain concentrations of antiepileptic drugs were measured by HPLC to exclude any pharmacokinetic contribution to the observed effect. ACEA (5 mg/kg, i.p.) + PMSF (30 mg/kg, i.p.) significantly potentiated the anticonvulsant potency of levetiracetam (P<0.05), but not that of clobazam, lacosamide, phenobarbital, tiagabine or valproate in the 6-Hz corneal stimulation model. Moreover, ACEA+PMSF did not significantly affect total brain concentrations of levetiracetam in mice. No behavioral side effects were observed in animals receiving combinations of the studied antiepileptic drugs with ACEA+PMSF. In conclusion, the combined administration of ACEA+PMSF with levetiracetam is associated with beneficial anticonvulsant pharmacodynamic interaction in the 6-Hz corneal stimulation model. The selective activation of cannabinoid CB1 receptor-mediated neurotransmission in the brain may enhance levetiracetam-related suppression of seizures in epilepsy patients, contributing to the efficacious treatment of epilepsy in future.

Development of Highly Affine and Selective Fluorinated Cannabinoid Type 2 Receptor Ligands.

Cannabinoid type 2 receptors (CB2 receptors) are involved in various pathological processes, and the visualization of their in vivo availability with positron emission tomography (PET) is of high interest. The study focuses on the introduction of fluorine into the structure of the highly affine and selective CB2 receptor ligand N-(adamantan-1-yl)-5-ethyl-2-methyl-1-phenyl-1H-imidazole-4-carboxamide (5). A novel series of compounds was developed by modifying (i) the adamantane-3-position, (ii) the imidazole-N-phenyl ring, and (iii) the imidazole-2-position, and the impact on the CB2 binding affinity and selectivity toward cannabinoid type 1 receptors (CB1) was evaluated. This study identified compound 15 as one of the most potent (Ki(CB2) = 0.29 nM) and selective (CB1/CB2 > 10000) CB2 receptor ligands discovered so far, eligible for the development of an 18F-labeled PET radiotracer.

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.

Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity

The cannabinoid CB2 receptor (CB2R) represents a promising therapeutic target for various forms of tissue injury and inflammatory diseases. Although numerous compounds have been developed and widely used to target CB2R, their selectivity, molecular mode of action and pharmacokinetic properties have been poorly characterized. Here we report the most extensive characterization of the molecular pharmacology of the most widely used CB2R ligands to date. In a collaborative effort between multiple academic and industry laboratories, we identify marked differences in the ability of certain agonists to activate distinct signalling pathways and to cause off-target effects. We reach a consensus that HU910, HU308 and JWH133 are the recommended selective CB2R agonists to study the role of CB2R in biological and disease processes. We believe that our unique approach would be highly suitable for the characterization of other therapeutic targets in drug discovery research.

Synthetic Cannabinoid Receptor Agonists and Antagonists: Implication in CNS Disorders.

Since the discovery of the cannabinoid receptors, numerous studies associate the endocannabinoid system with several physiological and pathological processes including cancer, appetite, fertility, memory, neuropathic and inflammatory pain, obesity, and neurodegenerative diseases. Over the last two decades, several researches have been dedicated extensively on the cannabinoid receptors ligands since the direct activation of cannabinoid receptors results in several beneficial effects, in the brain and in the periphery. The cannabinoid CB1 and CB2 receptor synthetic ligands reported in this review have been collected by a wide research of scientific literature in particular in public database for patents and clinical trials. The references for patent numbers, clinical trial registry numbers, websites and scientific articles are reported in the reference section. During past years, cannabinoid CB1 and CB2 receptor ligands from plants or lab were rapidly developed and then various new structures were reported to be cannabinoids. However the CB1 receptor ligands have had a limited usefulness due to their psychotropic effects, dependence, and cognitive impairment. On the contrary the development of CB2 receptor ligands has been more productive. Furthermore peripherally restricted agonists as well as CB1 receptor positive or negative allosteric modulators were studied with the aim of eliminating the undesirable CB1 receptor central effects. The CB1 and CB2 receptor ligands offer several therapeutic opportunities for several CNS-related diseases. Based on the scientific literature, this review provides an overview of CB1 and CB2 receptor synthetic ligands obtained from drug research and in particular those synthesized for therapeutic purposes and potential clinical applications for central nervous system disorders.

CB1 ligands modulate learning and memory of OBX rats

Purpose. The brain endocannabinoid system has been shown to play a role in learning and memory processes, although the exact mechanisms by which it interferes in these processes are not well established. We aimed at studying the effects of CB1 receptor ligands on learning and memory of rats with an experimental model of depression - olfactory bulbectomy (OBX). Material and methods. Cannabinoid CB1 receptor agonist HU-210 (5 µg) and cannabinoid CB1 receptor antagonist SR 141716A (3 µg) were microinjected i.c.v. in male Wistar rats with olfactory bulbectomy (OBX) model of depression. A passive avoidance task (step through) was used as a test for learning and memory. Results. In the non-OBX group, HU-210 impaired learning and memory processes expressed by the shortened latency time on the retention tests (3 hours and 24 hours after training) and by the decreased percentage of rats that have reached the learning criterion, as compared to the saline-treated controls. SR 141716A did not affect significantly the performance of rats in the step-through task. In the OBX rats HU-210 prolonged the latency time as compared to the saline-treated OBX controls, while SR 141716A did not affect significantly the OBX-related learning and memory deficits. Conclusion. These findings suggest complex modulatory effect of CB1 receptor agonist on learning and memory processes in non-OBX and OBX rats.

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.