Mechanistic Insights into the Stimulant Properties of Novel Psychoactive Substances (NPS) and Their Discrimination by the Dopamine Transporter-In Silico and In Vitro Exploration of Dissociative Diarylethylamines.

Michelle A Sahai,Jolanta Opacka-Juffry,Neelakshi Dutta,Colin Davidson,Colin Davidson

doi:10.3390/brainsci8040063

Michelle A Sahai, Jolanta Opacka-Juffry + Show 3 more

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https://doi.org/10.3390/brainsci8040063

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Abstract

Novel psychoactive substances (NPS) may have unsuspected addiction potential through possessing stimulant properties. Stimulants normally act at the dopamine transporter (DAT) and thus increase dopamine (DA) availability in the brain, including nucleus accumbens, within the reward and addiction pathway. This paper aims to assess DAT responses to dissociative diarylethylamine NPS by means of in vitro and in silico approaches. We compared diphenidine (DPH) and 2-methoxydiphenidine (methoxphenidine, 2-MXP/MXP) for their binding to rat DAT, using autoradiography assessment of [125I]RTI-121 displacement in rat striatal sections. The drugs’ effects on electrically-evoked DA efflux were measured by means of fast cyclic voltammetry in rat accumbens slices. Computational modeling, molecular dynamics and alchemical free energy simulations were used to analyse the atomistic changes within DAT in response to each of the five dissociatives: DPH, 2-MXP, 3-MXP, 4-MXP and 2-Cl-DPH, and to calculate their relative binding free energy. DPH increased DA efflux as a result of its binding to DAT, whereas MXP had no significant effect on either DAT binding or evoked DA efflux. Our computational findings corroborate the above and explain the conformational responses and atomistic processes within DAT during its interactions with the dissociative NPS. We suggest DPH can have addictive liability, unlike MXP, despite the chemical similarities of these two NPS.

Highlights

A notable increase in the number of new psychoactive substances (NPS), formerly known as ‘legal highs’, ‘bath salts’ or ‘designer drugs’ ties in with the growing lines of evidence of their complex behavioural effects and health risks they may carry
N-methyl-D-aspartate receptor antagonism [22], their psychoactive effects can be influenced by their binding to the monoamine transporters, with DPH and 2-MXP having their highest affinity for the dopamine transporter (DAT), followed by the noradrenaline transporter (NET) and serotonin transporter (SERT) [30]
2-MXP have markedly different functional potencies at DAT, as represented by their IC50 values of 1.99 μM and 30 μM for DPH and 2-MXP, respectively, at human DAT stably expressed in HEK293 cells [22]

Summary

Introduction

A notable increase in the number of new psychoactive substances (NPS), formerly known as ‘legal highs’, ‘bath salts’ or ‘designer drugs’ ties in with the growing lines of evidence of their complex behavioural effects and health risks they may carry. Through minor chemical modification of the molecular structure of psychoactive drugs, different biological effects can be achieved, which includes the drug’s addictive liability. The latter links with the stimulant effects of drugs and involves the neurotransmitter dopamine. Stimulants have been known to raise dopamine availability in the brain, including the brain’s reward pathway that can be hijacked by stimulant. Brain Sci. 2018, 8, 63; doi:10.3390/brainsci8040063 www.mdpi.com/journal/brainsci. Brain Sci. 2018, 8, 63 drugs [1]. Perceptions of pleasure and reward are associated with the release of dopamine in the nucleus accumbens as part of the reward pathway; a similar phenomenon is implicated in responses to stimulants whose repeated use may lead to drug dependence [2]

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