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

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.