Abstract
Rationale
Antipsychotics help alleviate the positive symptoms associated with schizophrenia; however, their debilitating side effects have spurred the search for better treatment options. Novel compounds can be screened for antipsychotic potential in neuronal cell cultures and following acute N-methyl-D-aspartate (NMDA) receptor blockade with non-competitive antagonists such as MK-801 in rodent behavioral models. Given the known interactions between NMDA receptors and type 1 cannabinoid receptors (CB1R), compounds that modulate CB1Rs may have therapeutic potential for schizophrenia.
Objectives
This study assessed whether the CB1R positive allosteric modulator GAT211, when compared to ∆9-tetrahydrocannabinol (THC), has potential to reduce psychiatric behavioral phenotypes following acute MK-801 treatment in rats, and block hyperdopaminergic signalling associated with those behaviors.
Methods
The effects of GAT211 and THC on cellular signaling were compared in Neuro2a cells, and behavioral effects of GAT211 and THC on altered locomotor activity and prepulse inhibition of the acoustic startle response caused by acute MK-801 treatment were assessed in male, Long Evans rats.
Results
GAT211 limited dopamine D2 receptor-mediated extracellular regulated kinase (ERK) phosphorylation in Neuro2a cells, whereas THC did not. As expected, acute MK-801 (0.15 mg/kg) produced a significant increase in locomotor activity and impaired PPI. GAT211 treatment alone (0.3–3.0 mg/kg) dose-dependently reduced locomotor activity and the acoustic startle response. GAT211 (3.0 mg/kg) also prevented hyperlocomotion caused by MK-801 but did not significantly affect PPI impairments.
Conclusion
Taken together, these findings support continued preclinical research regarding the usefulness of CB1R positive allosteric modulators as antipsychotics.
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Funding
This work was supported by grants from the Saskatchewan Health Research Foundation and the University of Saskatchewan College of Medicine to RBL and JGH and the National Institutes of Health (EY024717) to GAT. DLM received scholarship funding from the University of Saskatchewan College of Medicine. AJR and GAS received scholarship funding from the Natural Sciences and Engineering Research Council of Canada.
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Supplementary Fig. 1
Schematics depicting the methods and timeline used to assess locomotor activity and prepulse inhibition (PPI). (a) Using the open field test (OFT), locomotor activity was first assessed at baseline (30 min). Next, treatments were randomly assigned and administered i.p. 5 min apart and given a 15 min break following injections. Rats were then returned to the OFT for a 120 min trial to assess the effect of treatment on distance traveled. (b) Prepulse inhibition (PPI) is a 22 min program that administers a series of pulses to assess startle reflex and PPI (the attenuation of startle amplitude by a prepulse). Pulses were administered pseudo-randomly and vary based on prepulse intensity (3, 6 and 12 dB) and prepulse interval (30, 50, 80 and 140 ms) preceding a 120 dB pulse. Injection procedures remained similar and PPI began 15 mins after the second injection. (JPG 53 kb)
Supplementary Fig. 2
Schematic shows a breakdown of PPI session. Each 22 min session included a series of low-dB prepulses followed by loud 120 dB pulses that invoked a startle response. The background noise was 70 dB throughout, and inter-trial intervals ranged from 3 to 14 s (average 7.5 s). (a) Sessions began with a 5 min period with six randomly administered 120 dB pulse-alone trials. Startle amplitude was averaged to calculate P120 Before. (b) 84 trials were presented pseudorandom across three categories: 120 dB pulse-alone (6 trials; average startle amplitude = P120 During); prepulse + pulse (72 trials); or no-stimulus (6 trials). Prepulse + pulse trials consisted of six of each prepulse Interval (30, 50, 80 or 140 ms) and Intensity (0 [alone trials], 3, 6 or 12 dB) combinations with the 120 dB pulses. (c) During the final 5 min an additional six pulse-alone trials were presented (average startle amplitude = P120 After) (Lins et al. 2017). (JPG 444 kb)
Supplementary Fig. 3
Graphs show the effects of MK-801 and GAT211 prepulse intensity on reactivity (acoustic startle response to the prepulse). (a) Prepulse intensity and GAT211 had no significant effect on reactivity; although, MK-801 significantly increased reactivity. (b) No additional main effects were observed. (JPG 80 kb)
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McElroy, D.L., Roebuck, A.J., Scott, G.A. et al. Antipsychotic potential of the type 1 cannabinoid receptor positive allosteric modulator GAT211: preclinical in vitro and in vivo studies. Psychopharmacology 238, 1087–1098 (2021). https://doi.org/10.1007/s00213-020-05755-x
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DOI: https://doi.org/10.1007/s00213-020-05755-x