What is in that Drink: The Biological Actions of Ethanol, Acetaldehyde, and Salsolinol

Deehan, Gerald A.; Brodie, Mark S.; Rodd, Zachary A.

doi:10.1007/978-3-642-28720-6_198

Cited by 21 publications

(14 citation statements)

References 125 publications

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“…All are well known antipsychotic drugs. The metabolites with the largest MCS (6 heavy atoms) are salsoline and salsolinol (which is not unreasonable, as they are condensation products of dopamine and acetaldehyde [83–87]). When this ‘whole-ring’ assumption is relaxed (Fig.…”

Section: Resultsmentioning

confidence: 99%

Analysis of drug–endogenous human metabolite similarities in terms of their maximum common substructures

O’Hagan

Kell

2017

J Cheminform

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In previous work, we have assessed the structural similarities between marketed drugs (‘drugs’) and endogenous natural human metabolites (‘metabolites’ or ‘endogenites’), using ‘fingerprint’ methods in common use, and the Tanimoto and Tversky similarity metrics, finding that the fingerprint encoding used had a dramatic effect on the apparent similarities observed. By contrast, the maximal common substructure (MCS), when the means of determining it is fixed, is a means of determining similarities that is largely independent of the fingerprints, and also has a clear chemical meaning. We here explored the utility of the MCS and metrics derived therefrom. In many cases, a shared scaffold helps cluster drugs and endogenites, and gives insight into enzymes (in particular transporters) that they both share. Tanimoto and Tversky similarities based on the MCS tend to be smaller than those based on the MACCS fingerprint-type encoding, though the converse is also true for a significant fraction of the comparisons. While no single molecular descriptor can account for these differences, a machine learning-based analysis of the nature of the differences (MACCS_Tanimoto vs MCS_Tversky) shows that they are indeed deterministic, although the features that are used in the model to account for this vary greatly with each individual drug. The extent of its utility and interpretability vary with the drug of interest, implying that while MCS is neither ‘better’ nor ‘worse’ for every drug–endogenite comparison, it is sufficiently different to be of value. The overall conclusion is thus that the use of the MCS provides an additional and valuable strategy for understanding the structural basis for similarities between synthetic, marketed drugs and natural intermediary metabolites. Electronic supplementary materialThe online version of this article (doi:10.1186/s13321-017-0198-y) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

Analysis of drug–endogenous human metabolite similarities in terms of their maximum common substructures

O’Hagan

Kell

2017

J Cheminform

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“…; Deehan et al . ). Furthermore, salsolinol stimulates firing rate of DA neurons ex vivo (Xie & Ye ; Xie et al .…”

Section: Introductionmentioning

confidence: 97%

“…; Hipólito et al . ; Deehan, Brodie & Rodd ). Indeed, brain salsolinol quantification following in vivo ethanol administration is still an unresolved issue (Lee et al .…”

Section: Introductionmentioning

confidence: 99%

Key role of salsolinol in ethanol actions on dopamine neuronal activity of the posterior ventral tegmental area

et al. 2013

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Ethanol excites dopamine (DA) neurons in the posterior ventral tegmental area (pVTA). This effect is responsible for ethanol's motivational properties and may contribute to alcoholism. Evidence indicates that catalase-mediated conversion of ethanol into acetaldehyde in pVTA plays a critical role in this effect. Acetaldehyde, in the presence of DA, condensates with it to generate salsolinol. Salsolinol, when administered in pVTA, excites pVTA DA cells, elicits DA transmission in nucleus accumbens and sustains its self-administration in pVTA. Here we show, by using ex vivo electrophysiology, that ethanol and acetaldehyde, but not salsolinol, failed to stimulate pVTA DA cell activity in mice administered α-methyl-p-tyrosine, a DA biosynthesis inhibitor that reduces somatodendritic DA release. This effect was specific for ethanol and acetaldehyde since morphine, similarly to salsolinol, was able to excite pVTA DA cells in α-methyl-p-tyrosine-treated mice. However, when DA was bath applied in slices from α-methyl-p-tyrosine-treated mice, ethanol-induced excitation of pVTA DA neurons was restored. This effect requires ethanol oxidation into acetaldehyde given that, when H2 O2 -catalase system was impaired by either 3-amino-1,2,4-triazole or in vivo administration of α-lipoic acid, ethanol did not enhance DA cell activity. Finally, high performance liquid chromatography-tandem mass spectrometry analysis of bath medium detected salsolinol only after co-application of ethanol and DA in α-methyl-p-tyrosine-treated mice. These results demonstrate the relationship between ethanol and salsolinol effects on pVTA DA neurons, help to untangle the mechanism(s) of action of ethanol in this area and contribute to an exciting research avenue prosperous of theoretical and practical consequences.

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“…The possible involvement of the ethanol metabolite acetaldehyde as a mediator of the reinforcing effects of ethanol was proposed over 40 years ago, and the ‘acetaldehyde hypothesis’ has been strengthened since then (reviewed by Correa et al . ; Deehan, Brodie & Rodd ). Studies in the late 1970s (Brown, Amit & Rockman ) showed that naïve rats maintained in operant chambers self‐administer acetaldehyde solutions into the cerebral ventricles.…”

Section: Introductionmentioning

confidence: 99%

“…; Deehan et al . ) demonstrated that rats selectively bred as alcohol drinkers (strain P of Indianapolis) placed in operant chambers self‐administer both ethanol and acetaldehyde into the brain ventral tegmental area (VTA). Most importantly, the reinforcing concentrations of acetaldehyde [(6–12) × 10 −6 M] are three orders of magnitude lower than those required for ethanol (17 × 10 −3 M) (Oster et al .…”

Section: Introductionmentioning

confidence: 99%

Long‐term inhibition of ethanol intake by the administration of an aldehyde dehydrogenase‐2 (ALDH2)‐coding lentiviral vector into the ventral tegmental area of rats

et al. 2014

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Previous studies suggest that acetaldehyde generated from ethanol in the brain is reinforcing. The present studies tested the feasibility of achieving a long-term reduction of chronic and post-deprivation binge ethanol drinking by a single administration into the brain ventral tegmental area (VTA) of a lentiviral vector that codes for aldehyde dehydrogenase-2 (ALDH2), which degrades acetaldehyde. The ALDH2 gene coding vector or a control lentiviral vector were microinjected into the VTA of rats bred for their alcohol preference. In the chronic alcohol administration model, naïve animals administered the control vector and subsequently offered 10% ethanol and water ingested 8-9 g ethanol/kg body weight/day. The single administration of the ALDH2-coding vector prior to allowing ethanol availability reduced ethanol drinking by 85-90% (P < 0.001) for the 45 days tested. In the post-deprivation binge-drinking model, animals that had previously consumed ethanol chronically for 81 days were administered the lentiviral vector and were thereafter deprived of ethanol for three 7-day periods, each interrupted by a single 60-minute ethanol re-access after the last day of each deprivation period. Upon ethanol re-access, control vector-treated animals consumed intoxicating 'binge' amounts of ethanol, reaching intakes of 2.7 g ethanol/kg body weight in 60 minutes. The administration of the ALDH2-coding vector reduced re-access binge drinking by 75-80% (P < 0.001). This study shows that endowing the ventral tegmental with an increased ability to degrade acetaldehyde greatly reduces chronic alcohol consumption and post-deprivation binge drinking for prolonged periods and supports the hypothesis that brain-generated acetaldehyde promotes alcohol drinking.

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What is in that Drink: The Biological Actions of Ethanol, Acetaldehyde, and Salsolinol

Cited by 21 publications

References 125 publications

Analysis of drug–endogenous human metabolite similarities in terms of their maximum common substructures

Analysis of drug–endogenous human metabolite similarities in terms of their maximum common substructures

Key role of salsolinol in ethanol actions on dopamine neuronal activity of the posterior ventral tegmental area

Long‐term inhibition of ethanol intake by the administration of an aldehyde dehydrogenase‐2 (ALDH2)‐coding lentiviral vector into the ventral tegmental area of rats

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