Positive allosteric modulation of cannabinoid type-1 receptors: Effects of GAT211 on MK-801-induced behaviors in rats
Date
2020-10-28
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
ORCID
0000-0002-9797-1676
Type
Thesis
Degree Level
Masters
Abstract
Antipsychotics help alleviate the positive symptoms associated with schizophrenia; however, their debilitating side effects spur the search for better treatment options. Acute N-methyl-D-aspartate receptor (NMDAR) blockade with noncompetitive antagonists such as MK-801 has been used to screen novel compounds for their antipsychotic potential in rodent models. Given interactions between NMDAR and cannabinoid type 1 receptors (CB1R), we tested the ability of GAT211, a CB1R positive allosteric modulator, to reverse two behavioural effects of acute MK-801 treatment, including: (1) increased locomotor activity; and (2) reduced prepulse inhibition (PPI) of the acoustic startle response. Male, Long Evans rats were treated with MK-801 (0.15 mg/kg) and/or GAT211 (0.3-3.0 mg/kg) and locomotor activity or PPI were assessed 15 min later. As expected, acute MK-801 produced a profound increase in locomotor activity and impaired PPI. GAT211 treatment alone dose-dependently reduced locomotor activity and the acoustic startle response. GAT211 (3.0 mg/kg) also blocked the exaggerated locomotor activity caused by MK-801 and showed some modest ability to normalize MK-801-induced PPI impairments. These findings support continued preclinical research regarding the usefulness of CB1R positive allosteric modulators as novel antipsychotic medications.
Description
Keywords
schizophrenia, antipsychotic, cannabis, THC, NMDA receptor, MK-801, CB1 receptor, GAT211, positive allosteric modulation, open field, acoustic startle, prepulse inhibition, locomotor activity
Citation
Degree
Master of Science (M.Sc.)
Department
Physiology
Program
Physiology