Cannabidiolic acid methyl ester (HU-580) treatment in two preclinical models of schizophrenia: the role of CB1 and 5-HT1A receptors

Richardson, Brandon (2023) Cannabidiolic acid methyl ester (HU-580) treatment in two preclinical models of schizophrenia: the role of CB1 and 5-HT1A receptors. Masters thesis, Memorial University of Newfoundland.

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Abstract

Schizophrenia is a heterogeneous psychiatric disorder that is difficult to treat, and current treatment options are limited in their efficacy due to unpleasant side effects. It is paramount that new treatments are discovered that are better tolerated and have a high degree of symptom relief. Schizophrenia pathology is extremely complex and involves down-regulated cannabinoid receptor 1 (CB1R) and up-regulated 5-hydroxytryptamine 1A receptor (5-HT1AR) in the prefrontal cortex (PFC). HU-580 is a newly synthesized cannabinoid compound that is an agonist to 5-HT1AR and an antagonist to CB1R with the potential to reverse schizophrenia pathology. We examined the potential of cannabidiolic acid methyl ester (HU-580) treatment in two preclinical models of schizophrenia using C57BL/6 mice. The models used were the N-methyl-D-aspartate receptor (NMDAR) antagonism using dizocilpine (MK-801) and the maternal immune activation (MIA) with a dual hit component. We investigated if these models would induce schizophrenia-like behaviors, receptor sensitization, and neurophysiology, and if these effects were reversed/blocked by HU-580. This study found that MK-801 induced hyperlocomotion, immobility, social withdrawal, novel object preference deficits, down-regulation of CB1R and 5-HT1AR, deficits in difference response on mismatch negativity. The MIA model induced social deficits, increased latency to enter a lit box compartment, novel object preference deficits, increased escape behavior, down-regulated CB1R, and up regulated 5-HT1AR. HU-580 blocked the effects of MK-801 in hyperlocomotion, immobility, and cognitive deficits, and CB1R/5-HT1AR down-regulation. HU-580 also prevented MIA induced anxiety-like behavior, cognitive deficits and 5-HT1AR up-regulation. This study supports the involvement of CB1R and 5-HT1AR in the PFC in schizophrenia mouse models and provides evidence for the efficacy of HU-580 treatment.

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