Ethanol-Dependent Synthesis of Salsolinol in the Posterior Ventral Tegmental Area as Key Mechanism of Ethanol’s Action on Mesolimbic Dopamine
Abnormal consumption of ethanol, the ingredient responsible for alcoholic drinks’ addictive liability, causes millions of deaths yearly. Ethanol’s addictive potential is triggered through activation, by a still unknown mechanism, of the mesolimbic dopamine (DA) system, part of a key motivation circu...
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doaj-5fa21095866a4f958e6429d5b4799ea42021-06-28T04:30:35ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2021-06-011510.3389/fnins.2021.675061675061Ethanol-Dependent Synthesis of Salsolinol in the Posterior Ventral Tegmental Area as Key Mechanism of Ethanol’s Action on Mesolimbic DopamineValentina Bassareo0Valentina Bassareo1Roberto Frau2Riccardo Maccioni3Pierluigi Caboni4Cristina Manis5Alessandra T. Peana6Rossana Migheli7Simona Porru8Elio Acquas9Elio Acquas10Center of Excellence for the Study of Neurobiology of Addiction, University of Cagliari, Cagliari, ItalyDepartment of Biomedical Sciences, University of Cagliari, Cagliari, ItalyDepartment of Biomedical Sciences, University of Cagliari, Cagliari, ItalyDepartment of Life and Environmental Sciences, University of Cagliari, Cagliari, ItalyDepartment of Life and Environmental Sciences, University of Cagliari, Cagliari, ItalyDepartment of Life and Environmental Sciences, University of Cagliari, Cagliari, ItalyDepartment of Chemistry and Pharmacy, University of Sassari, Sassari, ItalyDepartment of Experimental Medical and Surgical Sciences, University of Sassari, Sassari, ItalyDepartment of Life and Environmental Sciences, University of Cagliari, Cagliari, ItalyCenter of Excellence for the Study of Neurobiology of Addiction, University of Cagliari, Cagliari, ItalyDepartment of Life and Environmental Sciences, University of Cagliari, Cagliari, ItalyAbnormal consumption of ethanol, the ingredient responsible for alcoholic drinks’ addictive liability, causes millions of deaths yearly. Ethanol’s addictive potential is triggered through activation, by a still unknown mechanism, of the mesolimbic dopamine (DA) system, part of a key motivation circuit, DA neurons in the posterior ventral tegmental area (pVTA) projecting to the ipsilateral nucleus accumbens shell (AcbSh). The present in vivo brain microdialysis study, in dually-implanted rats with one probe in the pVTA and another in the ipsilateral or contralateral AcbSh, demonstrates this mechanism. As a consequence of the oral administration of a pharmacologically relevant dose of ethanol, we simultaneously detect a) in the pVTA, a substance, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), untraceable under control conditions, product of condensation between DA and ethanol’s first by-product, acetaldehyde; and b) in the AcbSh, a significant increase of DA release. Moreover, such newly generated salsolinol in the pVTA is responsible for increasing AcbSh DA release via μ opioid receptor (μOR) stimulation. In fact, inhibition of salsolinol’s generation in the pVTA or blockade of pVTA μORs prevents ethanol-increased ipsilateral, but not contralateral, AcbSh DA release. This evidence discloses the long-sought key mechanism of ethanol’s addictive potential and suggests the grounds for developing preventive and therapeutic strategies against abnormal consumption.https://www.frontiersin.org/articles/10.3389/fnins.2021.675061/fullacetaldehydebrain microdialysisdopamineethanolμ opioid receptorsnucleus accumbens shell |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Valentina Bassareo Valentina Bassareo Roberto Frau Riccardo Maccioni Pierluigi Caboni Cristina Manis Alessandra T. Peana Rossana Migheli Simona Porru Elio Acquas Elio Acquas |
spellingShingle |
Valentina Bassareo Valentina Bassareo Roberto Frau Riccardo Maccioni Pierluigi Caboni Cristina Manis Alessandra T. Peana Rossana Migheli Simona Porru Elio Acquas Elio Acquas Ethanol-Dependent Synthesis of Salsolinol in the Posterior Ventral Tegmental Area as Key Mechanism of Ethanol’s Action on Mesolimbic Dopamine Frontiers in Neuroscience acetaldehyde brain microdialysis dopamine ethanol μ opioid receptors nucleus accumbens shell |
author_facet |
Valentina Bassareo Valentina Bassareo Roberto Frau Riccardo Maccioni Pierluigi Caboni Cristina Manis Alessandra T. Peana Rossana Migheli Simona Porru Elio Acquas Elio Acquas |
author_sort |
Valentina Bassareo |
title |
Ethanol-Dependent Synthesis of Salsolinol in the Posterior Ventral Tegmental Area as Key Mechanism of Ethanol’s Action on Mesolimbic Dopamine |
title_short |
Ethanol-Dependent Synthesis of Salsolinol in the Posterior Ventral Tegmental Area as Key Mechanism of Ethanol’s Action on Mesolimbic Dopamine |
title_full |
Ethanol-Dependent Synthesis of Salsolinol in the Posterior Ventral Tegmental Area as Key Mechanism of Ethanol’s Action on Mesolimbic Dopamine |
title_fullStr |
Ethanol-Dependent Synthesis of Salsolinol in the Posterior Ventral Tegmental Area as Key Mechanism of Ethanol’s Action on Mesolimbic Dopamine |
title_full_unstemmed |
Ethanol-Dependent Synthesis of Salsolinol in the Posterior Ventral Tegmental Area as Key Mechanism of Ethanol’s Action on Mesolimbic Dopamine |
title_sort |
ethanol-dependent synthesis of salsolinol in the posterior ventral tegmental area as key mechanism of ethanol’s action on mesolimbic dopamine |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Neuroscience |
issn |
1662-453X |
publishDate |
2021-06-01 |
description |
Abnormal consumption of ethanol, the ingredient responsible for alcoholic drinks’ addictive liability, causes millions of deaths yearly. Ethanol’s addictive potential is triggered through activation, by a still unknown mechanism, of the mesolimbic dopamine (DA) system, part of a key motivation circuit, DA neurons in the posterior ventral tegmental area (pVTA) projecting to the ipsilateral nucleus accumbens shell (AcbSh). The present in vivo brain microdialysis study, in dually-implanted rats with one probe in the pVTA and another in the ipsilateral or contralateral AcbSh, demonstrates this mechanism. As a consequence of the oral administration of a pharmacologically relevant dose of ethanol, we simultaneously detect a) in the pVTA, a substance, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), untraceable under control conditions, product of condensation between DA and ethanol’s first by-product, acetaldehyde; and b) in the AcbSh, a significant increase of DA release. Moreover, such newly generated salsolinol in the pVTA is responsible for increasing AcbSh DA release via μ opioid receptor (μOR) stimulation. In fact, inhibition of salsolinol’s generation in the pVTA or blockade of pVTA μORs prevents ethanol-increased ipsilateral, but not contralateral, AcbSh DA release. This evidence discloses the long-sought key mechanism of ethanol’s addictive potential and suggests the grounds for developing preventive and therapeutic strategies against abnormal consumption. |
topic |
acetaldehyde brain microdialysis dopamine ethanol μ opioid receptors nucleus accumbens shell |
url |
https://www.frontiersin.org/articles/10.3389/fnins.2021.675061/full |
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