Antipsychotic potential of the type 1 cannabinoid receptor positive allosteric modulator GAT211: preclinical in vitro and in vivo studies.
Dan L McElroy, Andrew J Roebuck, Gavin A Scott, Quentin Greba, Sumanta Garai, Eileen M Denovan-Wright, Ganesh A Thakur, Robert B Laprairie, John G Howland
Psychopharmacology April 2021 DOI: 10.1007/s00213-020-05755-x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study combining in vitro cell assays and in vivo rodent behavioral experiments Peer reviewed |
|---|---|
| Population | Neuro2a cells and male Long Evans rats |
| Interventions | GAT211 THC MK-801 |
| Dose | GAT211 0.3-3.0 mg/kg; MK-801 0.15 mg/kg |
| Topics | Cannabis |
| Keywords | Acoustic startle Mk-801 Nmda receptor Open field Prepulse inhibition Schizophrenia |
| Key findings | GAT211, a CB1R positive allosteric modulator, limited dopamine D2 receptor-mediated ERK phosphorylation in Neuro2a cells, unlike THC, and in male Long Evans rats dose-dependently reduced locomotor activity and acoustic startle, and at 3.0 mg/kg prevented MK-801-induced hyperlocomotion, but did not significantly affect MK-801-induced prepulse inhibition impairments. The authors argue these findings support continued preclinical research into CB1R positive allosteric modulators as antipsychotics. |
Abstract
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. 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. 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. 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. Taken together, these findings support continued preclinical research regarding the usefulness of CB1R positive allosteric modulators as antipsychotics.