EPV933
MM120 (lysergide D-tartrate) Receptor Binding and Evaluation in the Rat Following 13-weeks of Administration
J. Tripp 1, G. Smagin 1,*
1Non-Clinical, MindMed, New York, United States
Introduction: 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-HT1A, 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-HT2A and 5-HT1A 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-HT2A and 5-HT1A ex vivo receptor occupancy (RO) was measured by incubation of brain sections with [3H]8-OH-DPAT or [3H]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 [3H]Ketanserin at 6 mg/kg daily (p < 0.05), compared to vehicle and 6 mg/kg weekly groups, indicating a lower 5-HT2AR density. 5-HT1AR density revealed with [3H]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-HT2ARs in cortex and hippocampus, while 5-HT1ARs were affected only at the 6 mg/kg dose.
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Conclusions: The study demonstrates that 5-HT2AR downregulation may be responsible for the tolerance development after the repeated dosing and reduced abuse potential of MM120.
Disclosure of Interest: J. Tripp Shareolder of: 100%, Employee of: 100%, G. Smagin Shareolder of: 100%, Employee of: 100%