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

• Published in: Molecular neurobiology Vol. 56; no. 11; pp. 7251 - 7266
• Main Authors: Kruk-Slomka, Marta, Banaszkiewicz, Izabela, Slomka, Tomasz, Biala, Grazyna
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.11.2019; Springer Nature B.V
• Subjects: 2-Arachidonoylglycerol; Adrenal glands; Amidohydrolases - antagonists & inhibitors; Amidohydrolases - metabolism; Anandamide; Animals; Avoidance Learning - drug effects; Benzamides - administration & dosage; Benzamides - pharmacology; Benzamides - therapeutic use; Benzodioxoles - administration & dosage; Benzodioxoles - pharmacology; Benzodioxoles - therapeutic use; Biomedical and Life Sciences; Biomedicine; Cannabinoid CB1 receptors; Cannabinoid CB2 receptors; Carbamates - administration & dosage; Carbamates - pharmacology; Carbamates - therapeutic use; Cell Biology; Cognition - drug effects; Cognitive ability; Dizocilpine; Dizocilpine Maleate - administration & dosage; Dizocilpine Maleate - pharmacology; Dizocilpine Maleate - therapeutic use; Endocannabinoid system; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Fatty acids; Fatty-acid amide hydrolase; Glutamic acid receptors (ionotropic); Hydrolase; Inhibitors; Injections; Ligands; Lipase; Locomotor activity; Male; Memory; Memory - drug effects; Mental disorders; Mice; Motor Activity - drug effects; N-Methyl-D-aspartic acid receptors; Neurobiology; Neurology; Neurosciences; Piperidines - administration & dosage; Piperidines - pharmacology; Piperidines - therapeutic use; Rodents; Schizophrenia; Schizophrenia - drug therapy; Schizophrenia - physiopathology; Schizophrenia-like symptoms; MK-801; FAAH; MAGL; Mice; Endocannabinoids
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-019-1596-0

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.