Effects of pimavanserin, xanomeline and highly-purified plant-derived cannabidiol on MK-801-induced behaviours in mice relevant to psychosis

Background: Psychosis, as a comorbidity, is seen in many neuropsychiatric and neurodegenerative disorders and is often treated with dopamine D 2 receptor (D 2 R) antagonists, which could aggravate Alzheimer’s disease and Parkinson’s disease (PD) symptoms. Hence, there is a need for new treatments with a non-D 2 R antagonist-related mechanism of action. Recently approved drugs for psychosis in PD, including pimavanserin (PIM), and for schizophrenia, xanomeline-trospium, offer advances since they lack D 2 R antagonism but both carry associated risks. The highly-purified, plant-derived form of cannabidiol (hpCBD; Epidiolex ® ) has a different safety profile, does not inhibit D 2 R and has demonstrated antipsychotic effects in patients with psychosis. Aims: To systematically assess the potential antipsychotic-like effects of hpCBD, alongside newer non-D 2 antagonist drugs approved for PD psychosis (PIM) and schizophrenia psychosis (xanomeline oxalate (XAN)) in the same set of standardised preclinical assays. Methods: MK-801-induced hyperlocomotion and pre-pulse inhibition (PPI) deficits in male C57BL/6J mice were assessed following PIM (0.1, 0.3, 1 mg/kg s.c.), XAN (1, 3, 10 mg/kg s.c.) or hpCBD (50, 100, 200 mg/kg i.p.) administration. Locomotor activity was measured by infrared photobeams and Laboratory Animal Behaviour Observation Registration and Analysis System, and PPI was measured in acoustic startle chambers using a variable pre-pulse intensity protocol. Results: PIM, XAN (all doses) and hpCBD (200 mg/kg) attenuated MK-801 hyperlocomotion ( p < 0.01). PPI deficits, at various pre-pulse intensities, were attenuated by PIM (all doses), XAN 10 mg/kg and hpCBD 200 mg/kg ( p < 0.05). Conclusion: These results suggest that hpCBD, like PIM and XAN, demonstrates putative antipsychotic-like activity in classic mouse assays relevant to psychosis, consistent with positive clinical data in patients with psychosis.