Ethanol-dependent synthesis of salsolinol in the posterior ventral tegmental area as the key mechanism of ethanol's action on mesolimbic dopamine

Abnormal consumption of ethanol, the ingredient responsible for alcoholic drinks’ 82 addictive liability, causes millions of deaths yearly. Ethanol’s addictive potential is 83 84 triggered through activation, by a still unknown mechanism, of the mesolimbic dopamine 85 (DA) system, part of a key motivation circuit, DA neurons in the posterior ventral 86 tegmental area (pVTA) projecting to the ipsilateral nucleus accumbens shell (AcbSh). 87 The present in vivo brain microdialysis study, in dually-implanted rats with one probe 88 in the pVTA and another in the ipsilateral or contralateral AcbSh, demonstrates this 89 90 mechanism. As a consequence of the oral administration of a pharmacologically 91 relevant dose of ethanol, we simultaneously detect a) in the pVTA, a substance, 92 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), untraceable under 93 control conditions, product of condensation between DA and ethanol’s first by-product, 94 95 acetaldehyde; and b) in the AcbSh, a significant increase of DA release. Moreover, such 96 newly generated salsolinol in the pVTA is responsible for increasing AcbSh DA release 97 via μ opioid receptor (μOR) stimulation. In fact, inhibition of salsolinol’s generation 98 in the pVTA or blockade of pVTA μORs prevents ethanol-increased ipsilateral, but 99 not contralateral, AcbSh DA release. This evidence discloses the long-sought key 100 101 mechanism of ethanol’s addictive potential and suggests the grounds for developing 102 preventive and therapeutic strategies against abnormal consumption.