805. Rapid Antidepressant-Like Effects of 5-MeO-DMT Require Both 5-HT1A and 5-HT2A Receptors
Abstract
Abstract Background Recent clinical trials show that 5-MeO-DMT produces rapid antidepressant effects, yet the receptor mechanisms underlying these outcomes remain incompletely defined. Although 5-MeO-DMT is a high-affinity agonist at multiple serotonergic receptors, the relative contribution of 5-HT1A and 5-HT2A receptor signaling to its antidepressant-like actions has not been causally established. Aims & Objectives The primary objective of this study was to determine the necessity of 5-HT1A and 5-HT2A receptor activation for the rapid antidepressant-like effects of 5-MeO-DMT. A secondary objective was to examine how receptor-specific antagonism modulates associated serotonergic behavioral outputs. Method Male and female C57BL/6 mice received injections (i.p.) of vehicle or 5-MeO-DMT (1, 5, or 10 mg/kg) and were assessed in the open field test (OFT) for locomotion. A second cohort was evaluated for head twitch response (HTR) for 60 min then tested in the forced swim test (FST). A third cohort was pretreated with saline, WAY-100635 (0.3 mg/kg), MDL-100907 (0.2 mg/kg), SB-269970 (1 mg/kg), or BD1047 (3 mg/kg) followed by vehicle or 5-MeO-DMT (10 mg/kg) 30 min later. HTR was recorded for 60 min, followed by FST. In a subset of mice, in vivo extracellular electrophysiological recordings were obtained from the prefrontal cortex (PFC) following 5-MeO-DMT (10 mg/kg) administration. Results In the OFT, 5-MeO-DMT (10 mg/kg) decreased locomotor activity, [F(15, 165) = 14.11, p < 0.0001], up to 50 min (p = 0.0338) establishing a return to normal by 60 min. In the HTR, 5-MeO-DMT dose-dependently increased HTR in the first 10 min only, [F(3, 29) = 18.92, p < 0.0001]. In the FST, only 10 mg/kg of 5-MeO-DMT (M = 126.2, SD = 31.23) significantly decreased immobility time as compared to vehicle (M = 156.5, SD = 18.35), [F(3, 49) = 4.086, p = 0.0115]. When pre-treated with saline, [F(3, 37) = 7.332, p = 0.0006], 5-MeO-DMT (10 mg/kg) significantly reduced immobility (p = 0.0266), and both WAY-100635 (M = 174, SD = 43.39) and MDL-100907 (M = 193.2, SD = 29.46) blocked 5-MeO-DMT (M = 112.0, SD = 35.10) from reducing immobility time. Preliminary data shows that SB-269970 (M = 125.9, SD = 39.50) and BD1047 (M = 137.5, SD = 38.41) did not block the effect and were comparable to 5-MeO-DMT alone. Preliminary prefrontal cortex electrophysiological recordings from putative pyramidal neurons (n = 2) revealed a transient increase in firing (by 263.97, ± 52.7 %) followed by a sustained suppression (8.22 ± 8.22 % of basal firing) lasting up to 60 min, temporally aligned with the antidepressant-like behavioral window. Discussion & Conclusions Results establish that 5-HT1A and 5-HT2A receptors mediate the rapid antidepressant-like effects of 5-MeO-DMT. The divergence from HTR indicates that serotonergic behavioral outputs can be mechanistically dissociated from antidepressant-like efficacy.