Skip to main content
Canna~Fangled Abstracts

Antipsychotic potential of the type 1 cannabinoid receptor positive allosteric modulator GAT211: preclinical in vitro and in vivo studies

By January 13, 2021January 15th, 2021No Comments
. 2021 Jan 13.

doi: 10.1007/s00213-020-05755-x.

Online ahead of print.
Dan L McElroy 1, Andrew J Roebuck 2, Gavin A Scott 3, Quentin Greba 1, Sumanta Garai 4, Eileen M Denovan-Wright 5, Ganesh A Thakur 4, Robert B Laprairie 5 6, John G Howland 7
Affiliations 

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.

 

Keywords: Acoustic startle, Cannabis, MK-801, NMDA receptor, Open field, Prepulse inhibition, Schizophrenia, THC

References

    1. Ahmari SE, Risbrough VB, Geyer MA, Simpson HB (2012) Impaired sensorimotor gating in unmedicated adults with obsessive-compulsive disorder. Neuropsychopharmacology 37:1216–1223. https://doi.org/10.1038/npp.2011.308 – DOI – PubMed – PMC
    1. Al-Amin HA, Schwarzkopf SB (1996) Effects of the PCP analog dizocilpine on sensory gating: potential relevance to clinical subtypes of schizophrenia. Biol Psychiatry 40:744–754. https://doi.org/10.1016/0006-3223(95)00485-8 – DOI – PubMed
    1. Bagher AM, Laprairie RB, Kelly MEM, Denovan-Wright EM (2013) Co-expression of the human cannabinoid receptor coding region splice variants (hCB1) affects the function of hCB1 receptor complexes. Eur J Pharmacol 721:341–354. https://doi.org/10.1016/j.ejphar.2013.09.002 – DOI – PubMed
    1. Bagher AM, Laprairie RB, Toguri JT et al (2017) Bidirectional allosteric interactions between cannabinoid receptor 1 (CB1) and dopamine receptor 2 long (D2L) heterotetramers. Eur J Pharmacol 813:66–83. https://doi.org/10.1016/j.ejphar.2017.07.034 – DOI – PubMed
    1. Ballendine SA, Greba Q, Dawicki W et al (2015) Behavioral alterations in rat offspring following maternal immune activation and ELR-CXC chemokine receptor antagonism during pregnancy: implications for neurodevelopmental psychiatric disorders. Prog Neuro-Psychopharmacol Biol Psychiatry 57:155–165. https://doi.org/10.1016/j.pnpbp.2014.11.002 – DOI

Leave a Reply