Contribution of serotonin receptor subtypes to hallucinogenic activity of 25I-NBOMe and to its effect on neurotransmission

Monika Herian,Alejandro González-Marín,Adam Wojtas,Mateusz Skawski,Krystyna Gołembiowska,Małgorzata Katarzyna Sobocińska

doi:10.1007/s43440-020-00181-4

Monika Herian, Alejandro González-Marín + Show 4 more

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https://doi.org/10.1007/s43440-020-00181-4

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Abstract

Background4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25I-NBOMe) is a potent serotonin (5-HT) receptor agonist with hallucinogenic properties. The aim of our research was to examine the role of the 5-HT2A, 5-HT2C and 5-HT1A serotonin receptor subtypes in 25I-NBOMe hallucinogenic activity and its effect on dopamine (DA), 5-HT and glutamate release in the rat frontal cortex.MethodsHallucinogenic activity was investigated using the wet dog shake (WDS) test. The release of DA, 5-HT and glutamate in the rat frontal cortex was studied using a microdialysis in freely moving rats. Neurotransmitter levels were analyzed by HPLC with electrochemical detection. The selective antagonists of the 5-HT2A, 5-HT2C and 5-HT1A serotonin receptor subtypes: M100907, SB242084 and WAY100635, respectively were applied through a microdialysis probe.ResultsThe WDS response to 25I-NBOMe (1 and 3 mg/kg) was significantly reduced by local administration of M100907 and SB242084 (100 nM). The 25I-NBOMe-induced increase in glutamate, DA and 5-HT release was inhibited by M100907 and SB242084. WAY100635 had no effect on 25I-NBOMe-induced WDS and glutamate release, while it decreased DA and 5-HT release from cortical neuronal terminals.ConclusionThe obtained results suggest that 5-HT2A and 5-HT2C receptors play a role in 25I-NBOMe-induced hallucinogenic activity and in glutamate, DA and 5-HT release in the rat frontal cortex as their respective antagonists attenuated the effect of this hallucinogen. The disinhibition of GABA cells by the 5-HT1A receptor antagonist seems to underlie the mechanism of decreased DA and 5-HT release from neuronal terminals in the frontal cortex.

Highlights

4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25I-NBOMe) is a synthetic N-methoxybenzyl derivative of 2C-I (4-iodo-2,5-dimethoxyphenethylamine), a compound from the phenylalkylamine family and a potent 5-HT receptor agonist. 25I-NBOMe exhibits high in vitro binding
The glutamatergic system appears to play a role in the effects of serotonergic hallucinogens since in vivo studies have shown that the stimulation of cortical 5-HT2A receptors caused the release of glutamate [6, 7, 9]. 25I-NBOMe is a potent 5-HT2A receptor agonist with sub-nanomolar affinity and it is slightly weaker at 5-HT2C receptors, while showing low μM affinity at 5-HT1A receptors [1]
We hypothesized that 25I-NBOMe at a dose of 1 mg/kg exerted its effect on wet dog shake (WDS) and glutamate release via the 5-HT2A receptors, while at higher doses, the response was negatively modulated via the 5-HT2C and 5-HT1A receptors

Summary

Introduction

4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25I-NBOMe) is a synthetic N-methoxybenzyl derivative of 2C-I (4-iodo-2,5-dimethoxyphenethylamine), a compound from the phenylalkylamine family and a potent 5-HT receptor agonist. 25I-NBOMe exhibits high in vitro binding. Serotonin-2A receptors are expressed mainly on the apical dendrites of pyramidal cells in layer V of the cerebral cortex [3] with a minor localization to GABAergic interneurons [4, 5] Their activation leads to enhancement of cortical glutamate release, which is a common mechanism of action of hallucinogens [6,7,8,9]. There are studies confirming that 25I-NBOMe, through its agonist activity at the 5-HT2A receptor, produces dosedependent increases in HTR/WDS episodes as well as back muscle contractions (BMC) in rodents [6, 13, 18, 19]. Our previous study demonstrated that 25I-NBOMe exerted a potent effect on cortical glutamate, DA and 5-HT levels and induced hallucinogenic activity [6].

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