Ligand-specific effects of 5-HT2A receptor antagonists on fear extinction in C57BL/6J mice: Comparative insights from MDL 11,939 and MDL 100,907
Anastasia Tyulmenkova, Robert W. Stackman
bioRxiv (Cold Spring Harbor Laboratory) July 3, 2026 preprint DOI: 10.64898/2026.06.29.735330 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study |
|---|---|
| Population | Adult C57BL/6J mice |
| Interventions | MDL 11 939 (Glemanserin) MDL 100 907 (Volinanserin) SB 242084 |
| Dose | MDL 11,939: 1.0 mg/kg; MDL 100,907: 0.01 mg/kg; SB 242084: two doses (not specified) |
| Measures | conditioned freezing responses |
| Topics | Serotonin |
| Keywords | Extinction optical mineralogy Antagonism Receptor antagonist Stimulus psychology Pharmacology Freezing behavior Classical conditioning |
| Key findings | Repeated administration of the mixed 5-HT2A/2C antagonist MDL 11,939 impaired fear extinction in mice, while the selective 5-HT2A antagonist MDL 100,907 and the selective 5-HT2C antagonist SB 242084 did not significantly alter extinction learning. |
Abstract
Abstract Serotonin (5-HT) 2A receptors (5-HT 2 AR) modulate corticolimbic circuits regulating fear extinction. Although activation of these receptors has been shown to facilitate fear extinction, the behavioral consequences of 5-HT 2 AR antagonism during extinction is not well defined. Here, we examined the systemic effects of two 5-HT 2 A receptor antagonists, the mixed 5-HT 2 A/ 2 C antagonist MDL 11,939 (Glemanserin) and the selective 5-HT 2 A antagonist MDL 100,907 (Volinanserin) on fear extinction in adult C57BL/6J mice. Prior to drug administration, mice assigned to future treatment groups acquired comparable conditioned freezing responses during delay fear conditioning. Twenty-four hours later, acute administration of MDL 11,939 (1.0 mg/kg) or MDL 100,907 (0.01 mg/kg) increased freezing to the first conditioned stimulus (CS) presentation on Extinction Day 1, indicating enhanced expression of conditioned fear. However, acquisition of fear extinction differed between the respective cohorts of mice treated with the two 5-HT 2 AR antagonists. Repeated administration of MDL 11,939 significantly impaired extinction, as evidenced by increased freezing across extinction trials and an increased number of trials required to reach extinction criterion. In contrast, MDL 100,907 has reported affinity for did not significantly alter extinction under either acute or repeated dosing conditions. Because MDL 11,939 has reported affinity for 5-HT 2 C receptors, we tested potential contributions of 5-HT 2 C receptor antagonism in a separate cohort of mice using two doses of the selective 5-HT 2 C antagonist, SB 242084. Neither dose affected conditioned fear expression, extinction learning, or trials required to reach extinction criterion. Together, these findings demonstrate ligand-specific and dose-dependent effects of 5-HT 2 AR antagonism on fear extinction and suggest that distinct intracellular receptor signaling pathways may differentially regulate extinction-related behavior. Highlights MDL 11,939 and MDL 100,907 differentially affect fear extinction behavior Repeated MDL 11,939 impairs extinction learning in C57BL/6J mice MDL 100,907 did not significantly alter extinction learning Selective 5-HT 2 C antagonism does not influence extinction Ligand-dependent 5-HT2A signaling shapes extinction outcomes
Comparable studies
Other preclinical and animal studies on serotonin, most cited first.
| Study | Year | Design | Participants |
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| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |