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DC Field | Value | Language |
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dc.contributor.author | Loi, B | - |
dc.contributor.author | Sahai, MA | - |
dc.contributor.author | De Luca, MA | - |
dc.contributor.author | Shiref, H | - |
dc.contributor.author | Opacka-Juffry, J | - |
dc.date.accessioned | 2024-04-02T17:14:19Z | - |
dc.date.available | 2024-04-02T17:14:19Z | - |
dc.date.issued | 2020-06-05 | - |
dc.identifier | ORCiD: Michelle Sahai https://orcid.org/0000-0002-2898-3112 | - |
dc.identifier | 806 | - |
dc.identifier.citation | Loi, B. et al. (2020) 'The Role of Dopamine in the Stimulant Characteristics of Novel Psychoactive Substances (NPS)—Neurobiological and Computational Assessment Using the Case of Desoxypipradrol (2-DPMP)', Frontiers in Pharmacology, 11, 806, pp. 1 - 13. doi: 10.3389/fphar.2020.00806. | en_US |
dc.identifier.uri | https://bura.brunel.ac.uk/handle/2438/28676 | - |
dc.description | Data Availability Statement: The datasets generated for this study are available on request to the corresponding author. | en_US |
dc.description.abstract | Stimulant drugs, including novel psychoactive substances (NPS, formerly “legal highs”) have addictive potential which their users may not realize. Stimulants increase extracellular dopamine levels in the brain, including the reward and addiction pathways, through interacting with dopamine transporter (DAT). This work aimed to assess the molecular and atomistic mechanisms of stimulant NPS actions at DAT, which translate into biological outcomes such as dopamine release in the brain’s reward pathway. We applied combined in vitro, in vivo, and in silico methods and selected 2-diphenylmethylpiperidine (2-DPMP) as an example of stimulant NPS for this study. We measured in vitro binding of 2-DPMP to rat striatum and accumbens DAT by means of quantitative autoradiography with a selective DAT-radioligand [125I]RTI-121. We evaluated the effects of intravenously administered 2-DPMP on extracellular dopamine in the accumbens-shell and striatum using in vivo microdialysis in freely moving rats. We used dynamic modeling to investigate the interactions of 2-DPMP within DAT, in comparison with cocaine and amphetamine. 2-DPMP potently displaced the radioligand in the accumbens and striatum showing dose-dependence from 0.3 to 30 μM. IC50 values were: 5.65 × 10-7M for accumbens shell and 6.21 × 10-7M for dorsal striatum. Dose-dependent responses were also observed in accumbens-shell and striatum in vivo, with significant increases in extracellular dopamine levels. Molecular dynamics simulations identified contrasting conformational changes of DAT for inhibitors (cocaine) and releasers (amphetamine). 2-DPMP led to molecular rearrangements toward an outward-facing DAT conformation that suggested a cocaine-type effect. The present combination of molecular modeling with experimental neurobiological procedures allows for extensive characterization of the mechanisms of drug actions at DAT as the main molecular target of stimulants, and provides an insight into the role of dopamine in the molecular and neurobiological mechanisms of brain responses to stimulant NPS that have addictive potential. Such knowledge reveals the risk of addiction related to NPS use. The research presented here can be adapted for other psychostimulants that act at their membrane protein targets. | en_US |
dc.description.sponsorship | This project was supported in part by grants of the European Commission (Drug Prevention and Information Programme 2014–2016; contract JUST/2013/DPIP/AG/4823; EUMADNESS project). Further financial support was provided by the EU Commission‐targeted call on cross-border law enforcement cooperation in the field of drug trafficking—DG Justice/DG Migrations and Home Affairs (JUST/2013/ISEC/ DRUGS/AG/6429) Project EPS/NPS (Enhancing Police Skills concerning Novel Psychoactive Substances; NPS), and by the Drug Policies Department, Presidency of the Council of Ministers, Italy (project: “Effects of NPS: development of a multicentre research for the information enhancement of the Early Warning System” to ML), and RAS-FSC 2014-2020 to ML (Codice intervento: RC_CRP_034; CUP RASSR03071). The following computational resources are gratefully acknowledged: ARCHER granted via the UK High-End Computing Consortium for Biomolecular Simulation, HECBioSim (http://hecbiosim.ac.uk), supported by EPSRC (grant no. EP/L000253/1). | en_US |
dc.format.extent | 1 - 13 | - |
dc.format.medium | Electronic | - |
dc.language | English | - |
dc.language.iso | en_US | en_US |
dc.publisher | Frontiers Media | en_US |
dc.rights | Copyright © 2020 Loi, Sahai, De Luca, Shiref and Opacka-Juffry. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. | - |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | - |
dc.subject | addiction | en_US |
dc.subject | autoradiography | en_US |
dc.subject | brain | en_US |
dc.subject | dopamine transporter | en_US |
dc.subject | microdialysis | en_US |
dc.subject | molecular modelling | en_US |
dc.subject | cocaine | en_US |
dc.subject | amphetamine | en_US |
dc.title | The Role of Dopamine in the Stimulant Characteristics of Novel Psychoactive Substances (NPS)—Neurobiological and Computational Assessment Using the Case of Desoxypipradrol (2-DPMP) | en_US |
dc.type | Article | en_US |
dc.identifier.doi | https://doi.org/10.3389/fphar.2020.00806 | - |
dc.relation.isPartOf | Frontiers in Pharmacology | - |
pubs.publication-status | Published | - |
pubs.volume | 11 | - |
dc.identifier.eissn | 1663-9812 | - |
dc.rights.license | https://creativecommons.org/licenses/by/4.0/legalcode.en | - |
dc.rights.holder | Loi, Sahai, De Luca, Shiref and Opacka-Juffry | - |
Appears in Collections: | Dept of Life Sciences Research Papers |
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FullText.pdf | Copyright © 2020 Loi, Sahai, De Luca, Shiref and Opacka-Juffry. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. | 1.82 MB | Adobe PDF | View/Open |
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