Four Novel Synthetic Tryptamine Analogs Induce Head-Twitch Responses and Increase 5-HTR2a in the Prefrontal Cortex in Mice

Abstract

Tryptamines are monoamine alkaloids with hallucinogenic properties and are widely abused worldwide. To hasten the regulations of novel substances and predict their abuse potential, we designed and synthesized four novel synthetic tryptamine analogs: Pyrrolidino tryptamine hydrochloride (PYT HCl), Piperidino tryptamine hydrochloride (PIT HCl), N,N-dibutyl tryptamine hydrochloride (DBT HCl), and 2-Methyl tryptamine hydrochloride (2-MT HCl). Then, we evaluated their rewarding and reinforcing effects using the conditioned place preference (CPP) and self-administration (SA) paradigms. We conducted an open field test (OFT) to determine the effects of the novel compounds on locomotor activity. A head-twitch response (HTR) was also performed to characterize their hallucinogenic properties. Lastly, we examined the effects of the compounds on 5-HTR1a and 5-HTR2a in the prefrontal cortex using a quantitative real-time polymerase chain reaction (qRT-PCR) assay. None of the compounds induced CPP in mice or initiated SA in rats. PYT HCl and PIT HCl reduced the locomotor activity and elevated the 5-HTR1a mRNA levels in mice. Acute and repeated treatment with the novel tryptamines elicited HTR in mice. Furthermore, a drug challenge involving a 7-day abstinence from drug use produced higher HTR than acute and repeated treatments. Both the acute treatment and drug challenge increased the 5-HTR2a mRNA levels. Ketanserin blocked the induced HTR. Taken together, the findings suggest that PYT HCl, PIT HCl, DBT HCl, and 2-MT HCl produce hallucinogenic effects via 5-HTR2a stimulation, but may have low abuse potential.

25B‐NBOMe, a novel N‐2‐methoxybenzyl‐phenethylamine (NBOMe) derivative, may induce rewarding and reinforcing effects via a dopaminergic mechanism: Evidence of abuse potential

“…Drugs were administered either intraperitoneally (ip; eg, for CPP, HTR, EEG, western blotting, and qRT‐PCR experiments) or intravenously (iv; ie, for the SA test). Doses were determined based on previously published findings evaluating the rewarding, reinforcing, 14,24–25 and hallucinogenic 26,27 properties of similar compounds.…”

“…Doses were determined based on previously published findings evaluating the rewarding, reinforcing, 14,24,25 and hallucinogenic 26,27 properties of similar compounds.…”

Two newly-emerging substituted phenethylamines MAL and BOD induce differential psychopharmacological effects in rodents

“…The test consisted of three phases: (a) habituation (days 1-3) and pre-conditioning (day 4; 15 min), (b) conditioning (days 5-10; 30 min), and (c) post-conditioning (day 11; 15 min). The protocol used was in accordance with previous studies (Abiero et al, 2019b(Abiero et al, , 2019cCustodio et al, 2017), although some modifications were included. Briefly, mice were allowed to explore the compartments for 15 min during the habituation phase.…”

Bacterially Derived Tryptamine Increases Mucus Release by Activating a Host Receptor in a Mouse Model of Inflammatory Bowel Disease

“…It is too early to directly extrapolate these findings to humans despite encouraging evidence from our study. Future studies can also help verify whether microbial metabolite mimicry through production of synthetic tryptamine analogs ( Abiero et al., 2019 ) could be used as a potential pharmaceutic modality to improve gut inflammatory conditions.…”