Ethanol-Dependent Synthesis of Salsolinol in the Posterior Ventral Tegmental Area as Key Mechanism of Ethanol's Action on Mesolimbic Dopamine

Valentina Bassareo; Roberto Frau; Riccardo Maccioni; Pierluigi Caboni; Cristina Manis; Alessandra T Peana; Rossana Migheli; Simona Porru; Elio Acquas

doi:10.3389/fnins.2021.675061

Ethanol-Dependent Synthesis of Salsolinol in the Posterior Ventral Tegmental Area as Key Mechanism of Ethanol's Action on Mesolimbic Dopamine

Front Neurosci. 2021 Jun 28:15:675061. doi: 10.3389/fnins.2021.675061. eCollection 2021.

Authors

Affiliations

¹ Center of Excellence for the Study of Neurobiology of Addiction, University of Cagliari, Cagliari, Italy.
² Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
³ Department of Life and Environmental Sciences, University of Cagliari, Cagliari, Italy.
⁴ Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy.
⁵ Department of Experimental Medical and Surgical Sciences, University of Sassari, Sassari, Italy.

Abstract

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.

Keywords: acetaldehyde; brain microdialysis; dopamine; ethanol; nucleus accumbens shell; posterior ventral tegmental area; salsolinol; μ opioid receptors.