Abstract
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.
Highlights
Schizophrenia is a chronic psychiatric disorder with heterogeneous background and is expressed as a combination of diverse symptoms
We evaluated the influence of an acute administration of fatty acid hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibitors on the long-term memory acquisition, and we assessed the impact of these inhibitors on the memory impairment provoked by an acute injection of MK-801
We evaluated the influence of an acute administration of FAAH and MAGL inhibitors on the locomotion of mice
Summary
Schizophrenia is a chronic psychiatric disorder with heterogeneous background and is expressed as a combination of diverse symptoms. The signs of schizophrenia are formally divided into three distinct symptom clusters: positive, negative, and cognitive [1]. The negative symptoms are characterized by social withdrawal and anhedonia. The cognitive symptoms include deficits in semantic. Schizophrenia is a widely prevalent psychiatric disorder whose etiology and management has been still in large part unknown. Pharmacological studies of antipsychotic drugs have fueled hypothesis focused on neurotransmitter mechanisms which underlying pathophysiology of schizophrenia. They include alterations in dopamine (DA), glutamate (Glu), acetylcholine (ACh), serotonin (5-HT), and gammaaminobutyric acid (GABA) neurotransmission [4, 5]
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