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.
Highlights
Ethanol, key ingredient of alcoholic drinks, is one of the most used and abused psychoactive substances worldwide and underlies the potential of alcoholic drinks to trigger their abnormal/heavy consumption (Abrahao et al, 2017)
To directly test this hypothesis (Polache and Granero, 2013; Peana et al, 2016), we envisioned to detect salsolinol and DA through microdialysis probes implanted in the pVTA and accumbens shell (AcbSh), respectively, of the same side or of the opposite side of the rat brain, taking advantage of the mostly ipsilateral ventral tegmental area (VTA)–AcbSh projections (Geisler and Zahm, 2005; Ikemoto, 2007; Breton et al, 2019)
The results disclose for the first time that this systemic administration of ethanol determines the appearance of salsolinol, a molecule undetectable in pVTA dialysates under control conditions, no matter whether in dialysates of the same or of the opposite side with respect to that where we could simultaneously detect the increase of AcbSh DA release
Summary
Key ingredient of alcoholic drinks, is one of the most used and abused psychoactive substances worldwide and underlies the potential of alcoholic drinks to trigger their abnormal/heavy consumption (Abrahao et al, 2017). This evidence suffers a lack of general consensus (Söderpalm and Ericson, 2013) and of a specific molecular mechanism (Israel et al, 2015; Peana et al, 2017b, 2019) This notwithstanding, the ability of ethanol to stimulate DA neurons in the pVTA (Gessa et al, 1985), activate DA transmission in the AcbSh (Howard et al, 2008; Bassareo et al, 2017), and elicit DA-mediated locomotor activity (Carlsson et al, 1972; Sánchez-Catalán et al, 2009) has been mechanistically related to ethanol’s main metabolite, acetaldehyde. Salsolinol is selfadministered by rats in the pVTA (Rodd et al, 2008), and its pVTA administration promotes voluntary binge-like ethanol intake (Quintanilla et al, 2016)
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