Resumen
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.
Idioma original | English |
---|---|
Páginas (desde-hasta) | 1087-1098 |
Número de páginas | 12 |
Publicación | Psychopharmacology |
Volumen | 238 |
N.º | 4 |
DOI | |
Estado | Published - abr. 2021 |
Nota bibliográfica
Funding Information: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.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.
ASJC Scopus Subject Areas
- Pharmacology
PubMed: MeSH publication types
- Journal Article