Salsolinol and dopamine in rat medial basal hypothalamus after chronic ethanol exposure

doi:10.1016/0024-3205(85)90115-8

Life Sciences

Volume 36, Issue 4, 28 January 1985, Pages 309-314

https://doi.org/10.1016/0024-3205(85)90115-8 Get rights and content

Abstract

Endogenous levels of salsolinol and dopamine were measured by a gas chromatography/mass spectrometry (GC/MS) - selected ion monitoring technique using deuterated internal standards in Long Evans rats chronically exposed to ethanol for ten months. Chronic ethanol exposure produced significant increases of dopamine and salsolinol concentrations in the medial basal hypothalamus but not striatum. The data suggest that the occurrence of salsolinol in rat brain tissue is a consequence of an $in$ $vivo$ Pictet-Spengler cyclization.

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Consistent with the sex differences observed in ethanol clearance, ethanol metabolites, such as tetrahydroisoquinolines (TIQs) may have pharmacokinetic differences which could contribute to the sex differences in fear behavior observed in these studies. TIQs are generally thought to be neurotoxic and were increased in many areas of the CNS, including limbic structures, following chronic ethanol administration (Sjöquist et al., 1982; Myers et al., 1985). Similarly, the ethanol metabolite acetate increased adenosine in the CNS (Israel et al., 1994).
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Neurobiological aspects of ethanol-derived salsolinol
2019, Neuroscience of Alcohol: Mechanisms and Treatment
In spite of the enormous scientific interest raised by its widespread use, ethanol still remains, from the pharmacological and toxicological standpoints, an elusive molecule. Accordingly, its effects cannot be attributed only to actions onto specific targets (receptors, enzymes, channels, etc.) nor to the unique involvement of neurotransmitter systems (glutamate, GABA, dopamine, opioid peptides, etc.). Both the pharmacological and toxicological effects of ethanol, in fact, have also been related to its metabolic conversion into acetaldehyde, a highly reactive molecule that, besides other properties, shows the ability to condensate, spontaneously or enzymatically, with nucleophilic compounds to form tetrahydroisoquinolines. Among the latter, salsolinol has recently received a great deal of attention both for its neurobiological properties potentially related to alcoholism development and for its neurotoxicity. Accordingly, although detected at very low concentrations in ethanol-naïve subjects, salsolinol appears particularly enriched in the brain, in dopamine-containing nuclei where its main metabolites, N-methyl-salsolinol and 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion, may exert cytotoxic effects. This chapter recapitulates the most compelling evidence that relates ethanol-derived salsolinol to the neurobiological basis of alcoholism and to the suggested emergence of neurological disorders associated, in particular, to dopamine neurodegeneration.
Acetaldehyde production capacity of salivary microflora in alcoholics during early recovery
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This study investigated whether a relationship exists between the acetaldehyde production capacity of salivary microflora (sAPC) in recovering alcoholics, and craving, and/or resumption of drinking within 12 weeks after embarking on an abstinence-based treatment program. Serial sAPC measurements were determined by gas chromatography on spontaneous saliva samples of 30 male alcoholics on days 2, 4, 11, and 18 during a 21-day in-patient treatment program. Craving was measured simultaneously with the Penn Alcohol Craving Scale. Outcome over 12 weeks was assessed by telephone interviews. There was no significant change in sAPC values from day 2 to day 18, while craving scores decreased markedly between day 2 to day 4. Sixteen participants remained abstinent for the full 12 weeks. Statistically significant differences were found between the sAPC values of the group that remained abstinent and the group that resumed drinking within 12 weeks. The highest sAPC value measured on day 2 had a strong predictive value for maintained abstinence at 12 weeks for beer-only drinkers or drinkers consuming less than 320 g of alcohol per week. The study is the first investigation into a potential relationship between the acetaldehyde production capacity of salivary microflora and early resumption of drinking in recovering alcoholics. The findings suggest that such a relationship indeed exists for beer-only drinkers, possibly linked to lower alcohol intake, and that it is unrelated to withdrawal craving. sAPC is proposed as a candidate biomarker with diagnostic and/or prognostic potential.
Revisiting the controversial role of salsolinol in the neurobiological effects of ethanol: Old and new vistas
2012, Neuroscience and Biobehavioral Reviews
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To summarize, the reported data indicate that: (i) Sal is differentially distributed in human brain regions, with higher concentrations reported in DA rich regions, (ii) the levels of both enantiomers tend to be similar in areas with abundant DA whereas the predominance of R-Sal is observed in those areas with lower DA levels and (iii) some of the non-coincident results reported in relation to the magnitude of Sal levels could be attributed to the differences in analytical techniques, sampling protocol, handling and storage of the samples. A number of studies have also been devoted to detect and quantify Sal in the brain of rodents (Baum et al., 1999; DeCuypere et al., 2008; Haber et al., 1999; Lee et al., 2010; Matsubara et al., 1987; Myers et al., 1985; Rojkovicova et al., 2008; Starkey et al., 2006). These studies reported low Sal levels that are consistent with those reported in the human literature.
The possible involvement of salsolinol (Sal), an endogenous condensation product of ACD (the first metabolite of ethanol) and dopamine, in the neurochemical basis underlying ethanol action has been repeatedly suggested although it has not been unequivocally established, still being a controversial matter of debate. The main goal of this review is to evaluate the presumed contribution of Sal to ethanol effects summarizing the reported data since the discovery in the 1970s of Sal formation in vitro during ethanol metabolism until the more recent studies characterizing its behavioral and neurochemical effects. Towards this end, we first analyze the production and detection of Sal, in different brain areas, in basal conditions and after alcohol consumption, highlighting its presence in regions especially relevant in regulating ethanol-drinking behaviour and the importance of the newly developed methods to differentiate both enantiomers of Sal which could help to explain some previous negative findings. Afterwards, we review the behavioral and neurochemical studies. Finally, we present and discuss the previous and current enunciated mechanisms of action of Sal in the CNS.
Piecing together the puzzle of acetaldehyde as a neuroactive agent
2012, Neuroscience and Biobehavioral Reviews
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Salsolinol and THP thus might be regarded as direct and indirect acetaldehyde condensation products, respectively, and the improvements in modern analytical methods together with a body of experimental evidence indicate that both molecules represent useful lines of research. In this regard, one line of evidence originated from the observations that salsolinol and THP can be detected, respectively, in the rat brain after contingently self-administered acetaldehyde (Myers et al., 1985a,b; Cashaw, 1993) and noncontingently administered ethanol. In the Myers et al. (1985b) study, significant concentrations of salsolinol were detectable after i.v. self-administration of acetaldehyde (2.32 mg/kg/injection), but not ethanol (44.33 mg/kg/infusion), although these authors found detectable salsolinol concentrations in the brain of rats chronically treated with ethanol in another study (Myers et al., 1985a).
Mainly known for its more famous parent compound, ethanol, acetaldehyde was first studied in the 1940s, but then research interest in this compound waned. However, in the last two decades, research on acetaldehyde has seen a revitalized and uninterrupted interest. Acetaldehyde, per se, and as a product of ethanol metabolism, is responsible for many pharmacological effects which are not clearly distinguishable from those of its parent compound, ethanol. Consequently, the most recent advances in acetaldehyde's psychopharmacology have been inspired by the experimental approach to test the hypothesis that some of the effects of ethanol are mediated by acetaldehyde and, in this regard, the characterization of metabolic pathways for ethanol and the localization within discrete brain regions of these effects have revitalized the interest on the role of acetaldehyde in ethanol's central effects. Here we present and discuss a wealth of experimental evidence that converges to suggest that acetaldehyde is an intrinsically active compound, is metabolically generated in the brain and, finally, mediates many of the psychopharmacological properties of ethanol.
Alteration of selective neurotransmitters in fetal brains of prenatally alcohol-treated C57BL/6 mice: Quantitative analysis using liquid chromatography/tandem mass spectrometry
2010, International Journal of Developmental Neuroscience
Citation Excerpt :
We asked whether prenatal alcohol exposure alters the overall concentration of salsolinol. The local concentration of this isoquinoline derivative increases in the adult rat brain during ethanol intoxication (Collins and Kahn, 1982; Myers et al., 1985). This is assumed to result from the Pictet-Spengler condensation reaction between dopamine and acetaldehyde, a product of ethanol metabolism (Collins and Kahn, 1982).
We previously demonstrated that prenatal alcohol exposure results in brain defects at different embryonic stages. This study is aimed at characterizing the influence of prenatal alcohol exposure on the levels of several neurotransmitters at early embryonic stage 13 (E13). Pregnant C57BL/6 mice were exposed to either a 25% ethanol derived calorie diet (ALC) or pair-fed (PF) liquid diet from E7 to E13. At E13, fetal brains were collected from dams of the ALC and PF groups. Liquid chromatography/tandem mass spectrometry (LC–MS) was then used to evaluate neurotransmitter levels. This approach involved the use of an LC column in conjunction with multiple-reaction monitoring mass spectrometry. Quantitative analyses of catecholamines, idolamine, and amino acid neurotransmitters revealed significant reductions in the levels of dopamine (p = 0.004), norepinephrine (p = 0.0009), epinephrine (p = 0.0002), serotonin (p = 0.004), and GABA (p = 0.002) in the ALC group compared to the PF group. However, there was no significant change in the levels of glutamate in E13 fetal brains. These findings demonstrate that prenatal alcohol exposure reduces the concentrations of some catecholamines, idolamine, and amino acid neurotransmitters in E13 fetal brains. This study suggests that alterations of selective neurotransmitters may be the cause of abnormalities in brain function and behavior found in fetal alcohol spectrum disorders.

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Salsolinol and dopamine in rat medial basal hypothalamus after chronic ethanol exposure

Abstract

J. Chromatrogr. Biomed. Appl.

Lancet

Chromatogr. Biomed. Appl.

Science

Science

J. Biomed. Mass. Spec.

Ann. Chem.

J. Agric. Food Chem.

J. Agric. Food Chem.

IRCS Med. Sci. (Biochem.)