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Therapeutic-like activity of cannabidiolic acid methyl ester (HU-580) in the MK-801 mouse model of schizophrenia: role for cannabinoid CB1 and serotonin-1A receptors
  • Brandon Richardson,
  • Courtney Clarke,
  • Francis Bambico
Brandon Richardson
Memorial University of Newfoundland
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Courtney Clarke
Memorial University
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Francis Bambico
Memorial University

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Schizophrenia is an incurable psychotic illness. Those diagnosed have limited pharmacological treatment options, many of which do not provide long term relief and come with unpleasant side effects. The endocannabinoid and serotonergic systems are important neuromodulators in psychotic illness. We hypothesize that cannabidiolic acid methyl ester (HU-580) that exerts action on both these systems could have therapeutic potential by antagonizing cannabinoid receptor-1 (CB1R) and agonizing 5-hydroxytryptamine receptor-1A (5-HT1AR). We employed behavioural and brain protein analyses in male and female mice exposed to MK-801, which precipitated schizophrenia-related reactivity across a number of behavioural dimensions. C57BL/6 mice were subjected to a battery of behavioral tests, and we found that subchronic treatment of MK-801 (once daily for seven days) induced positive-like, negative-like, and cognitive-related behavioral deficits; primarily in females. Sub-chronic treatment of MK-801 (once daily for 17 days) induced positive- and negative-like behavioral deficits in females. Low-dose (0.01ug/kg) but not high-dose (0.05 ug/kg) treatment rescued female mice from schizophrenia-related behavioral deficits. Altogether, these data suggest that HU-580 may have dose-dependent antipsychotic-like potential that rely on mechanisms that recruit CB1R and 5-HT1AR.
10 Aug 2023Submitted to European Journal of Neuroscience
11 Aug 2023Assigned to Editor
11 Aug 2023Submission Checks Completed
12 Aug 2023Review(s) Completed, Editorial Evaluation Pending
12 Aug 2023Reviewer(s) Assigned
23 Oct 2023Editorial Decision: Revise Major