Modification of 5-methoxy-N,N-dimethyltryptamine-induced hyperactivity by monoamine oxidase A inhibitor harmaline in mice and the underlying serotonergic mechanisms

Abstract

Background 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and harmaline are indolealkylamine (IAA) drugs often abused together. Our recent studies have revealed the significant effects of co-administered harmaline, a monoamine oxidase inhibitor (MAOI), on 5-MeO-DMT pharmacokinetics and thermoregulation. This study was to delineate the impact of harmaline and 5-MeO-DMT on home-cage activity in mouse models, as well as the contribution of serotonin (5-HT) receptors. Methods Home-cage activities of individual animals were monitored automatically in the home cages following implantation of telemetry transmitters and administration of various doses of IAA drugs and 5-HT receptor antagonists. Area under the effect curve (AUEC) of mouse activity values were calculated by trapezoidal rule. Results High dose of harmaline (15 mg/kg, ip) alone caused an early-phase (0–45 min) hypoactivity in mice that was fully attenuated by 5-HT1A receptor antagonist WAY-100635, whereas a late-phase (45–180 min) hyperactivity that was reduced by 5-HT2A receptor antagonist MDL-100907. 5-MeO-DMT (10 and 20 mg/kg, ip) alone induced biphasic effects, an early-phase (0–45 min) hypoactivity that was completely attenuated by WAY-100635, and a late-phase (45–180 min) hyperactivity that was fully suppressed by MDL-100907. Interestingly, co-administration of MAOI harmaline (2–15 mg/kg) with a subthreshold dose of 5-MeO-DMT (2 mg/kg) induced excessive hyperactivities at late phase (45–180 min) that could be abolished by either WAY-100635 or MDL-100907. Conclusions Co-administration of MAOI with 5-MeO-DMT provokes excessive late-phase hyperactivity, which involves the activation of both 5-HT1A and 5-HT2A receptors.

The epidemiology of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) use: Benefits, consequences, patterns of use, subjective effects, and reasons for consumption

“…In terms of its pharmacological effects, 5-MeO-DMT is a potent, fast-acting, psychedelic substance (Ott, 2001a). In animal models, 5-MeO-DMT acts as a non-selective 5-HT agonist (Shen et al, 2011), active at both the 5-HT 1A and 5-HT 2A receptors (Jiang et al, 2016). 5-MeO-DMT appears to have a higher affinity for the 5-HT 1A receptor subtype (Spencer et al, 1987) and also inhibits the reuptake of 5-HT (Nagai et al, 2007).…”

Development of a mechanism-based pharmacokinetic/pharmacodynamic model to characterize the thermoregulatory effects of serotonergic drugs in mice

“…Higher dose combinations of harmaline (5 or 15 mg/kg) and 5-MeO-DMT (10 mg/kg) are toxic to both genotypes of mice 27 , 31 , 39 (and unpublished data). Such dose combinations caused a rapid increase of CBT (15–75 min) to an extremely high level ( e.g.…”

“…It has been shown that MAOI harmaline significantly enhances 5-MeO-DMT–induced hallucinogenic effects and toxicity 21 , 24 , 25 , 26 . Recent studies also demonstrate the influence of harmaline on 5-MeO-DMT–elicited neuropharmacological effects in animal models including thermoregulation and behaviors 31 , 39 , 40 , 41 , 42 , 43 as well as 5-MeO-DMT pharmacokinetics 27 , 29 , 43 . In the present study, a mathematical PK/PD model, which consists of an IDR model with baseline behavior, the adaptive feedback mechanism of the biological system, the impact of stress caused by handling and injection, and mechanistic actions of serotonergic drugs in thermomodulation, was developed and validated to characterize the relationship between drug concentrations and modulation of CBT by harmaline and 5-MeO-DMT, administered alone or in combination.…”

“…This developed PK/PD model was externally validated by comparing the simulated and experimentally-determined CBT profiles in mice treated with 10 mg/kg of harmaline alone, 5 mg/kg of 5-MeO-DMT alone, and 5 mg/kg of harmaline plus 5 mg/kg of 5-MeO-DMT that were all proven non-toxic by our previous 27 and pilot studies. The qualified model was further utilized to investigate the interactions between harmaline (2, 5 or 15 mg/kg) and 5-MeO-DMT (10 mg/kg), which was shown to be toxic to both genotypes of mice 27 , 31 , 39 . Simulations of harmaline and 5-MeO-DMT PK profiles were also conducted using our PK DDI model described recently 27 .…”

Behavioral Changes Over Time Following Ayahuasca Exposure in Zebrafish

“…However, 5HT1A receptors have been related to the behavioral alterations caused by this drug, such as hypoactivity ( Krebs-Thomson et al, 2006 ). Studies with mice found that administration of 5-Meo-DMT and harmaline reduce locomotion, but the effect is abolished by the administration of 5HT1A antagonists ( Krebs-Thomson et al, 2006 ; Jiang et al, 2016 ). Moreover, serotonin and mainly dopamine can cross-regulate acetylcholine ( Jackson et al, 1988 ; DeBoer et al, 1996 ).…”