(R)-Salsolinol, a product of ethanol metabolism, stereospecifically induces behavioral sensitization and leads to excessive alcohol intake

Abstract

Ethanol is oxidized in the brain to acetaldehyde, which can condense with dopamine to generate (R/S)-salsolinol [(RS)-SAL]. Racemic salsolinol [(RS)-SAL] is self-infused by rats into the posterior ventral tegmental area (VTA) at significantly lower concentrations than those of acetaldehyde, suggesting that (RS)-SAL is a most active product of ethanol metabolism. Early studies showed that repeated intraperitoneal or intra-VTA administration of (RS)-SAL (10 mg/kg) induced conditioned place preference, led to locomotor sensitization and increased voluntary ethanol consumption. In the present study, we separated the (R)- and (S)-enantiomers from a commercial (RS)-SAL using a high-performance liquid chromatography with electrochemical detection system fitted with a β-cyclodextrin-modified column. We injected (R)-SAL or (S)-SAL (30 pmol/1.0 μl) into the VTA of naïve UChB rats bred as alcohol drinkers to study whether one or both SAL enantiomers are responsible for the motivated behavioral effects, sensitization and increase in voluntary ethanol intake. The present results show that repeated administration of (R)-SAL leads to (1) conditioned place preference; (2) locomotor sensitization; and (3) marked increases in binge-like ethanol intake. Conversely, (S)-SAL did not influence any of these parameters. Overall, data indicate that (R)-SAL stereospecifically induces motivational effects, behavioral sensitization and increases ethanol intake.

Acquisition, Maintenance and Relapse-Like Alcohol Drinking: Lessons from the UChB Rat Line

“…Studies by Quintanilla et al (2016a), in UChB rats showed that the intra-cerebroventricular or systemic administration of ( R/S) -SAL increased the motivational effects of ethanol as shown by the place preference technique (Figure 5), in line with studies by Matsuzawa et al (2000) in Sprague-Dawley rats and by Hipólito et al (2011) in Wistar rats.…”

“…This effect was also observed by Myers and Melchior (1977) in Sprague-Dawley rats. Noteworthy, the high ethanol intakes are of the same order as those ingested by rats that had consumed ethanol for several weeks and were exposed to the ethanol deprivation condition followed by ethanol re-access ( vide infra ).Studies by Quintanilla et al (2016a), in UChB rats showed that the intra-cerebroventricular or systemic administration of ( R/S) -SAL increased the motivational effects of ethanol as shown by the place preference technique (Figure 5), in line with studies by Matsuzawa et al (2000) in Sprague-Dawley rats and by Hipólito et al (2011) in Wistar rats.Intracerebral administration studies in UChB rats showed that the ethanol motivational and intake sensitization effects of ( R/S) -SAL is also seen with R-SAL while the S-SAL enantiomer is inactive (Figure 6; Quintanilla et al, 2016a). Although the pharmacological mechanisms responsible for the action of (R/S )-SAL remain unclear, the specific effect of the R-enantiomer in inducing the motivational effects of ethanol, suggests that in vivo the chirality of the C-1 center of (R/S )-SAL plays an important role in changing its affinity for transporters or receptors associated with ethanol intake.…”

Racemic Salsolinol and its Enantiomers Act as Agonists of the μ-Opioid Receptor by Activating the Gi Protein-Adenylate Cyclase Pathway

“…An animal study performed in alcohol-preferring P rats showed that after 8 weeks of chronic ethanol consumption, there was a 2-fold increase in (S)-SAL levels in the midbrain, whereas a 1.6-fold increase was detected in (R)-SAL levels (Rojkovicova et al, 2008). In contrast to these findings, a recent behavioral study by Quintanilla et al (2016) found that (R)-SAL was the only enantiomer capable of inducing conditioned place preference after its intracerebral infusion into the VTA of rats. The reasons for these inconsistencies are unknown, but a possible explanation would be the existence of different molecular targets for (R)-SAL or its in vivo metabolism.…”

“…(R)-SAL and (S)-SAL were separated from the racemic solution by high-pressure liquid chromatography (HPLC) as described previously (Quintanilla et al, 2016). Briefly, a solution of (R/S)-SAL was injected into a NUCLEODEX β-cyclodextrin-modified column (Macherey-Nagel, Düren, Germany) kept at 20°C.…”

“…Animal studies have shown that chronic ethanol administration to rats results in a significant increase of SAL levels in dopamine-rich areas of the brain such as striatum, limbic forebrain and hypothalamus (Sjöquist et al, 1982; Matsubara et al, 1987), yielding increased amounts of SAL (Rojkovicova et al, 2008). Behavioral studies performed in rats have shown that SAL administration results in major increases in voluntary ethanol intake (Myers and Melchior, 1977; Quintanilla et al, 2014, 2016), locomotor activity (Hipólito et al, 2010; Quintanilla et al, 2014) and conditioned place preference (Matsuzawa et al, 2000; Quintanilla et al, 2014). Microdialysis studies have shown that microinjections of SAL into the ventral tegmental area (VTA) of rats result in an increased release of dopamine in the nucleus accumbens (Deehan et al, 2013), a common hallmark shared by different drugs of abuse, including ethanol (Di Chiara and Imperato, 1988).…”