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

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.