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

• Published in: Psychopharmacology 2021-04, Vol.238 (4), p.1087-1098
• Main Authors: McElroy, Dan L., Roebuck, Andrew J., Scott, Gavin A., Greba, Quentin, Garai, Sumanta, Denovan-Wright, Eileen M., Thakur, Ganesh A., Laprairie, Robert B., Howland, John G.
• Format: Article
• Language: English
• Subjects: Acoustic startle response; Allosteric properties; Allosteric proteins; Animal behavior; Animal models; Animals; Antipsychotic Agents - pharmacology; Antipsychotic drugs; Antipsychotics; Behavior, Animal - drug effects; Biomedical and Life Sciences; Biomedicine; Cannabinoid CB1 receptors; Cannabinoids; Cell Line; Dizocilpine; Dizocilpine Maleate; Dopamine D2 receptors; Dosage and administration; Dose-Response Relationship, Drug; Dronabinol - pharmacology; Drug receptors; Evaluation; Excitatory Amino Acid Antagonists; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - metabolism; Glutamic acid receptors; Glutamic acid receptors (ionotropic); Identification and classification; Indoles - pharmacology; Locomotor activity; Male; Mental disorders; Motor Activity - drug effects; N-Methyl-D-aspartic acid receptors; Neuromodulation; Neurosciences; Original Investigation; Pharmacology/Toxicology; Phenotypes; Phosphorylation; Prepulse Inhibition - drug effects; Psychiatry; Psychoses, Substance-Induced - drug therapy; Psychoses, Substance-Induced - psychology; Psychotropic drugs; Rats; Rats, Long-Evans; Receptor, Cannabinoid, CB1 - drug effects; Schizophrenia; Startle response; Tetrahydrocannabinol; THC
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-020-05755-x

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.