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

Int J Mol Sci. 2023 Jul 13;24(14):11400. doi: 10.3390/ijms241411400.

Abstract

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.

Keywords: FAAH and MAGL inhibitor; NMDA receptor hypofunction; endocannabinoids; mice; passive avoidance test; schizophrenia-like cognitive disorders.

MeSH terms

  • Amidohydrolases / metabolism
  • Animals
  • Dizocilpine Maleate / pharmacology
  • Endocannabinoids* / metabolism
  • Enzyme Inhibitors / pharmacology
  • Memory Disorders / drug therapy
  • Memory Disorders / etiology
  • Mice
  • Monoacylglycerol Lipases / metabolism
  • N-Methylaspartate
  • Schizophrenia* / drug therapy

Substances

  • Endocannabinoids
  • N-Methylaspartate
  • Dizocilpine Maleate
  • Enzyme Inhibitors
  • Monoacylglycerol Lipases
  • Amidohydrolases