Salsolinol, free of isosalsolinol, exerts ethanol-like motivational/sensitization effects leading to increases in ethanol intake.

Salsolinol is formed non-enzymatically when ethanol-derived acetaldehyde binds to dopamine, yielding 2 distinct products, i.e., salsolinol and isosalsolinol. Early animal studies, revealing that salsolinol promotes alcohol consumption and recent evidence that animals will readily self-administer salsolinol into the posterior ventral tegmental area (p-VTA) together with the finding that salsolinol is able to induce conditioned place preference and to increase locomotor activity, have outlined a role of salsolinol in the behavioral and neurobiological actions of ethanol. Until recently, the only commercially available salsolinol was a mixture containing 85% salsolinol and 10-15% isosalsolinol. The possibility thus exists that either salsolinol or isosalsolinol explains the reinforcing properties of ethanol. We report here that a newly available salsolinol is free of isosalsolinol. Thus, salsolinol, free of isosalsolinol, was injected intracerebrally (30 pmol/0.2 µL, into the ventral tegmental area [VTA]) or intraperitoneally (i.p.) (10 mg/kg) to naïve rats bred as alcohol drinkers to study salsolinol's motivational effects and its role on voluntary ethanol intake. Salsolinol produced conditioned place preference and increased locomotor activity, whether injected intra-VTA or intraperitoneally. Following systemic (i.p.) administration of 10 mg/kg salsolinol, this molecule was detected in vivo by microdialysis of neostriatum, reaching an estimated concentration of 100 nM in the dialyzate. These results indicate that systemically administered salsolinol is able to cross the blood-brain barrier (BBB). Repeated administration of salsolinol sensitized rats to the locomotor activity and led to increases in voluntary ethanol consumption, which was prevented by intra-VTA pretreatment with naltrexone.

Salsolinol and isosalsolinol: condensation products of acetaldehyde and dopamine. Separation of their enantiomers in the presence of a large excess of dopamine.

Dopamine (DA) condenses, at least in vitro, with acetaldehyde, the primary metabolite of ethanol, to form the regioisomers salsolinol (SAL) and isosalsolinol (isoSAL). An alternative in vivo route to SAL, requiring a decarboxylation step, has been suggested via condensation of DA with pyruvic acid. SAL has been proposed as a mediator of the rewarding effects of ethanol in the brain. We have now shown by HPLC, nuclear magnetic resonance (NMR) and mass spectrometry (MS) that the commercially available SAL contains about 10% of isoSAL, whose biological activity is unknown. If SAL is indeed the biologically active metabolite, rather than isoSAL, it is also unknown whether the rewarding molecule is (S)- or (R)-SAL. We have developed methodologies for the quantitative determination of DA, SAL and isoSAL using ion-pair reversed-phase HPLC, and for the separation of DA from (S)- and (R)-SAL and an isoSAL enantiomer on a ß-cyclodextrin-modified column, in both cases with electrochemical detection. A significant advance over earlier methods was achieved for the analysis of (S)- and (R)-SAL in the presence of a large excess of DA (100:1 DA-SAL ratio), as expected to occur in vivo, by suppressing the DA peak by selective derivatization with 2,3-naphthalenedicarboxaldehyde into a molecule that is electrochemically silent at the electrode potential used. The methodologies developed will allow the separation and determination of the pharmacological activity of these two products of condensation of acetaldehyde with DA. Further, the techniques for (S)- and (R)-SAL separation at a high DA:SA ratio will allow the existence of a putative (R)-SAL synthase to be determined and, if it exists, its role in alcoholism.