Therapeutic-like activity of cannabidiolic acid methyl ester in the MK-801 mouse model of schizophrenia: Role for cannabinoid CB1 and serotonin-1A receptors

Eur J Neurosci. 2024 May;59(9):2403-2415. doi: 10.1111/ejn.16278. Epub 2024 Feb 22.

Abstract

Schizophrenia is a psychotic disorder with an increasing prevalence and incidence over the last two decades. The condition presents with a diverse array of positive, negative, and cognitive impairments. Conventional treatments often yield unsatisfactory outcomes, especially with negative symptoms. We investigated the role of prefrontocortical (PFC) N-methyl-D-aspartate receptors (NMDARs) in the pathophysiology and development of schizophrenia. We explored the potential therapeutic effects of cannabidiolic acid (CBDA) methyl ester (HU-580), an analogue of CBDA known to act as an agonist of the serotonin-1A receptor (5-HT1AR) and an antagonist of cannabinoid type 1 receptor (CB1R). C57BL/6 mice were intraperitoneally administered the NMDAR antagonist, dizocilpine (MK-801, .3 mg/kg) once daily for 17 days. After 7 days, they were concurrently given HU-580 (.01 or .05 μg/kg) for 10 days. Behavioural deficits were assessed at two time points. We conducted enzyme-linked immunosorbent assays to measure the concentration of PFC 5-HT1AR and CB1R. We found that MK-801 effectively induced schizophrenia-related behaviours including hyperactivity, social withdrawal, increased forced swim immobility, and cognitive deficits. We discovered that low-dose HU-580 (.01 μg/kg), but not the high dose (.05 μg/kg), attenuated hyperactivity, forced swim immobility and cognitive deficits, particularly in female mice. Our results revealed that MK-801 downregulated both CB1R and 5-HT1AR, an effect that was blocked by both low- and high-dose HU-580. This study sheds light on the potential antipsychotic properties of HU-580, particularly in the context of NMDAR-induced dysfunction. Our findings could contribute significantly to our understanding of schizophrenia pathophysiology and offer a promising avenue for exploring the therapeutic potential of HU-580 and related compounds in alleviating symptoms.

Keywords: MK‐801; cannabidiolic acid methyl ester (HU‐580); cannabinoid CB1 receptor; mouse model; schizophrenia; serotonin‐1A receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology
  • Cannabinoids / pharmacology
  • Disease Models, Animal*
  • Dizocilpine Maleate* / pharmacology
  • Female
  • Male
  • Mice
  • Mice, Inbred C57BL*
  • Receptor, Cannabinoid, CB1* / agonists
  • Receptor, Cannabinoid, CB1* / metabolism
  • Receptor, Serotonin, 5-HT1A* / drug effects
  • Receptor, Serotonin, 5-HT1A* / metabolism
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Schizophrenia* / chemically induced
  • Schizophrenia* / drug therapy
  • Schizophrenia* / metabolism

Substances

  • Dizocilpine Maleate
  • Receptor, Serotonin, 5-HT1A
  • Receptor, Cannabinoid, CB1
  • Cannabinoids
  • Htr1a protein, mouse
  • Receptors, N-Methyl-D-Aspartate
  • Antipsychotic Agents