MM120 (lysergide D-tartrate) Receptor Binding and Evaluation in the Rat Following 13-weeks of Administration
J. Tripp, G. SmaginIntroduction
MM120 (lysergide D-tartrate, LSD, CAS 32426-57-6) is under development as a potential treatment for generalized anxiety disorder and major depressive disorder. MM120 may elicit profound lasting psychological changes through interaction with brain 5-HT 1A , 1B , 2A , 2C , 6 and 7 receptors, among others, while the complete mechanism is not clear.
Objectives
The study was performed to determine receptor occupancy and receptor density for 5-HT 2A and 5-HT 1A receptor in rats after chronic administration of MM120.
Methods
Rats were administered MM120 (0, 0.5, 2.0, 6.0 mg/kg) daily or weekly (6.0 mg/kg) for 13-weeks and tested for toxicity, neurological safety (functional observational battery [FOB]) or physiological states. 5-HT 2A and 5-HT 1A ex vivo receptor occupancy (RO) was measured by incubation of brain sections with [ 3 H]8-OH-DPAT or [ 3 H]Ketanserin and quantification of binding. Receptor density was then measured in cortical and hippocampal washed membranes.
Results
Chronic dosing showed no changes in body temperatures or FOB at week 13. Body weight changes were lower for 6 mg/kg daily group, but not weekly. Receptor density showed significantly lower binding of [
3
H]Ketanserin at 6 mg/kg daily (p < 0.05), compared to vehicle and 6 mg/kg weekly groups, indicating a lower 5-HT
2A
R density. 5-HT
1A
R density revealed with [
3
H]8-OH-DPAT binding was significantly lower in 6 mg/kg daily (p < 0.05) group, while other groups were unaffected. in vitro receptor binding and functional activity was evaluated and compared to other drugs of abuse. Chronic administration of MM120 at all doses significantly downregulated 5-HT
2A
Rs in cortex and hippocampus, while 5-HT
1A
Rs were affected only at the 6 mg/kg dose.
Image 1: Long description.