Effects of AM2389, a CB1 receptor full agonist, on psychosis-associated brain regions and memory function

Walid Yassine, DMSc, MMSc

McLean Hospital
Effects of AM2389, a CB1 receptor full agonist, on psychosis-associated brain regions and memory function

Scientific Abstract

Background: Clinical research shows that regular use of 9-tetrahydrocannabinol (THC), a CB1 receptor partial agonist, during adolescence increases the propensity for developing psychosis in adulthood. CB1 receptor expression is abundant in the hippocampus, and its alteration might be behind the structural and functional hippocampal changes reported in adolescent THC users, leading to cognitive and memory decline. The present study aimed to examine the effects of acute and chronic exposure to a high potency, long-acting CB1 receptor full agonist, AM2389, on the hippocampus and memory function.

Methods: Four experimentally naïve female rhesus monkeys, 4-4.5 years old at the start of the study, served as subjects. Monkeys were trained on a titrated delayed match to sample (TDMTS) task. After performance stabilized, a 3T magnetic resonance imaging scanner was used to acquire the anatomic data at baseline, after the first treatment (acute), after treatment for 30 days (chronic), and 30 days after AM2389 treatment was discontinued. Anatomical data were quality checked and extracted using AFNI to obtain the volumetric thickness values. Several regions implicated in psychosis including the hippocampus were used as regions of interest. Statistical analysis was performed using Prism 9.

Results: The results showed that Para hippocampal cortical volume was significantly different between the baseline and acute timepoints of administration (P = .006), but not between baseline and chronic or discontinuation, nor chronic and discontinuation timepoints. Analysis of the association between the parahippocampal cortex volumetric thickness and memory function revealed significant associations between cortical volume and mean titration (P< .001) and response rate (P= .04) values in the TDMTS task.

Conclusions: Acute administration of AM2389 alters the parahippocampal cortex and this change was found to be associated with memory performance decline. However, no long term effects of CB1 treatment on the parahippocampal cortex or memory were observed. These results provide valuable guidance for evaluating the contribution of CB1-mediated actions of THC to its effects on psychosis.

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Walid Yassine, DMSc, MMSc, Brian D. Kangas, PhD, Shan Jiang, BS, Spyros P. Nikas, PhD, Alexandros Makriyannis, PhD, Jack Bergman, PhD, Stephen J. Kohut, PhD

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