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Repeated salsolinol administration increases voluntary ethanol intake. (A) Rats pretreated with salsolinol into the VTA (30.0 pmol/0.2 mL) (days 1, 3, 8, 12; arrows) increased ethanol intake (60 min/day) during 7 consecutive days (gray bars), versus rats pretreated with aCSF into the VTA (0.2 mL) (days 1, 3, 8, 12; arrows) (white bars). (B)
Contexts in source publication
Context 1
... day 12, the same animals that had been treated with 3 salsolinol doses (on days 1, 3, and 8) to study its effect on locomotion, were treated (intra VTA or i.p.) with a last dose of salsolinol (or vehicle). From day 13th to day 19th, these rats were not treated and were allowed access to bottles containing water or ethanol to determine their voluntary ethanol intake. Fig. 6 shows ethanol intake displayed by rats on days 13e19 after the last dose of salsolinol (intra-VTA or i.p.) or vehicle (control group). Two-way ANOVA (drug pretreatment ? days) of data shown in Fig. 6A revealed that rats pretreated with salsolinol intra-VTA displayed a significantly higher ethanol intake compared to the aCSF-pretreated group Experiment 4 e Estimated concentrations of salsolinol in the dialyzates of brain and subcutaneous tissue following an i.p. dose of 10 mg/kg of ...
Context 2
... day 12, the same animals that had been treated with 3 salsolinol doses (on days 1, 3, and 8) to study its effect on locomotion, were treated (intra VTA or i.p.) with a last dose of salsolinol (or vehicle). From day 13th to day 19th, these rats were not treated and were allowed access to bottles containing water or ethanol to determine their voluntary ethanol intake. Fig. 6 shows ethanol intake displayed by rats on days 13e19 after the last dose of salsolinol (intra-VTA or i.p.) or vehicle (control group). Two-way ANOVA (drug pretreatment ? days) of data shown in Fig. 6A revealed that rats pretreated with salsolinol intra-VTA displayed a significantly higher ethanol intake compared to the aCSF-pretreated group Experiment 4 e Estimated concentrations of salsolinol in the dialyzates of brain and subcutaneous tissue following an i.p. dose of 10 mg/kg of ...
Context 3
... 5 e Effect of repeated intracerebral naltrexone (intra-VTA) and i.p. salsolinol treatment on alcohol intake Brain salsolinol following the systemic salsolinol administration could putatively act on many brain areas, where the effect of salso- linol can be modulated by opioid receptors (Hip?lito et al., 2010). We therefore investigated in na?ve rats whether the opioid receptors in the VTA were involved in the increases of ethanol intake induced by repeated salsolinol administration. Naltrexone (1.6 nM in 0.2 mL) was microinjected into the VTA 5 min prior to the administration of each of 4 repeated doses of salsolinol (10 mg/kg, i.p.) on days 1, 3, 8, and 12. From day 13th to day 19th, these rats were not treated and were exposed to a free-choice ethanol intake versus water on a limited- access (1 h) paradigm. All reported animals showed a correctly positioned intra-VTA cannula implantation. Fig. 2C shows the observed tip cannula placement. Fig. 8 shows ethanol intake by rats on days 13e19 after the last dose of naltrexone/salsolinol or naltrexone/saline pretreatment (control). Unlike the observation that salsolinol without naltrexone pretreatment (as shown above) induces a markedly increased ethanol voluntary intake (c.f. Fig. 6B versus Fig. 8), when the animals were previously pretreated with Rats pretreated with systemic salsolinol (10 mg/kg, i.p.) (days 1, 3, 8, 12; arrows) increased ethanol intake (60 min/day) during 7 consecutive days (gray bars), versus rats pretreated with saline (7 mL/kg, i.p.) (days 1, 3, 8, 12; arrows) (white bars). Data are means AE SEM and represent grams of total ethanol consumed per kilogram of body weight per 60 min. Asterisk indicates statistically significant differences between the salsolinol-pretreated and vehicle-pretreated animals in the experimental session: *p < 0.001 (two-way ...
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Citations
... This hypothesis was recently substantiated by multiple robust lines of evidence. The first line of evidence refers to experiments showing that systemic [36] or local [37] salsolinol administration elicits conditioned place preference, exerts alcohol-like motivational/sensitization effects [38,39] and leads to excessive alcohol intake [39]. The second line of evidence refers to an in-vitro electrophysiological study, in which the ability of alcohol to stimulate the firing rate of DA neurons of the pVTA critically depended on the availability of DA, as well as on the metabolic conversion of alcohol into acetaldehyde [40]. ...
The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A2A adenosine receptors (A2AR), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the A1R antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the A2AR antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of A2AR antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder.
... Previous in vivo microdialysis studies shown that (R/S)-salsolinol reaches detectable levels (100 nM) in the neostriatum following the systemic administration of (R/ S)-salsolinol (10 mg/kg, i.p.), isosalsolinol-free, providing evidence of the ability of salsolinol to cross the blood brain barrier (BBB) (Quintanilla et al. 2014). This result was supported by the demonstration that repeated intraperitoneal administration of (R/S)-salsolinol (10 mg/kg) elicited conditioned place preference and increased locomotor activity in a manner similar to that caused by the intra-VTA administration of repeated doses (30 pmol) of (R/S)-salsolinol in naive UChB rats (Quintanilla et al. 2014). ...
... Previous in vivo microdialysis studies shown that (R/S)-salsolinol reaches detectable levels (100 nM) in the neostriatum following the systemic administration of (R/ S)-salsolinol (10 mg/kg, i.p.), isosalsolinol-free, providing evidence of the ability of salsolinol to cross the blood brain barrier (BBB) (Quintanilla et al. 2014). This result was supported by the demonstration that repeated intraperitoneal administration of (R/S)-salsolinol (10 mg/kg) elicited conditioned place preference and increased locomotor activity in a manner similar to that caused by the intra-VTA administration of repeated doses (30 pmol) of (R/S)-salsolinol in naive UChB rats (Quintanilla et al. 2014). Moreover, repeated intraperitoneal (10 mg/kg) or intra-VTA (30 pmol) administration of (R/S)-salsolinol not only sensitized rats to the locomotor stimulating effect, but also elicited a marked increases of the acquisition of ethanol intake in the UChB rats. ...
... Moreover, repeated intraperitoneal (10 mg/kg) or intra-VTA (30 pmol) administration of (R/S)-salsolinol not only sensitized rats to the locomotor stimulating effect, but also elicited a marked increases of the acquisition of ethanol intake in the UChB rats. The administration of 4 doses of salsolinol either into the VTA (30 pmol), or systemically (10 mg/kg, i.p.), every 3 days to naive UChB rats increased subsequent voluntary ethanol intake by 200 to 250%, such that the rats ingested 2.5 g of ethanol/kg in 60 min an intake which remained constant for 1 week (the duration of follow-up) after discontinuing the salsolinol administration (Quintanilla et al. 2014). Given that in this study the estimated brain half-life of salsolinol was short (30-60 min), the finding that its effect on ethanol intake lasted at least 1 week suggests that it was not the salsolinol molecule per se that perpetuated the increased ethanol consumption. ...
Studies presented in this chapter show that: (1) in the brain, ethanol is metabolized by catalase to acetaldehyde, which condenses with dopamine forming salsolinol; (2) acetaldehyde-derived salsolinol increases the release of dopamine mediating, via opioid receptors, the reinforcing effects of ethanol during the acquisition of ethanol consumption, while (3) brain acetaldehyde does not influence the maintenance of chronic ethanol intake, it is suggested that a learned cue-induced hyperglutamatergic system takes precedence over the dopaminergic system. However, (4) following a prolonged ethanol deprivation, the generation of acetaldehyde in the brain again plays a role, contributing to the increase in ethanol intake observed during ethanol re-access, called the alcohol deprivation effect (ADE), a model of relapse behavior; (5) naltrexone inhibits the high ethanol intake seen in the ADE condition, suggesting that acetaldehyde-derived salsolinol via opioid receptors also contributes to the relapse-like drinking behavior. The reader is referred to glutamate-mediated mechanisms that trigger the cue-associated alcohol-seeking and that also contribute to triggering relapse.KeywordsAcquisition of ethanol intakeAlcohol deprivation effectAldehyde dehydrogenaseAminotriazoleBinge-like drinkingBrain acetaldehyde generationBrain salsolinolCatalaseDrug-seekingEthanol aversionGene therapyMaintenance of ethanol intakeNaltrexoneOpioid receptorPenicillamineReinforcing effect
... 64,70−73 Until recently there was no definitive evidence that another TIQ derivative, SAL, could or could not cross the BBB. 74 Neither Origitano et al. (1981) nor Song et al. (2006a) found any evidence that levels of (R/S)-SAL in the brain were increased by these compounds' intraperitoneal administration, prompting conclusions that SAL could not be transported across the BBB. 73,75 However, more recently Quintanilla et al. (2014) showed that systemically administered SAL, at 10 mg/kg, could cross the BBB in sufficient amounts for detection in vivo by microdialysis of neostriatum, reaching an estimated concentration of 100 nmol/L in the dialysate. ...
... 74 Neither Origitano et al. (1981) nor Song et al. (2006a) found any evidence that levels of (R/S)-SAL in the brain were increased by these compounds' intraperitoneal administration, prompting conclusions that SAL could not be transported across the BBB. 73,75 However, more recently Quintanilla et al. (2014) showed that systemically administered SAL, at 10 mg/kg, could cross the BBB in sufficient amounts for detection in vivo by microdialysis of neostriatum, reaching an estimated concentration of 100 nmol/L in the dialysate. 74 Moreover, exogenous SAL can alter laboratory animals' behavior, indicating that neuronal or glial enzymes could convert it to a potent neurotoxin and hence alter central dopaminergic pathways. ...
... 73,75 However, more recently Quintanilla et al. (2014) showed that systemically administered SAL, at 10 mg/kg, could cross the BBB in sufficient amounts for detection in vivo by microdialysis of neostriatum, reaching an estimated concentration of 100 nmol/L in the dialysate. 74 Moreover, exogenous SAL can alter laboratory animals' behavior, indicating that neuronal or glial enzymes could convert it to a potent neurotoxin and hence alter central dopaminergic pathways. Therefore, in principle, consumption of edibles that contain TIQ derivatives that may potentially be converted to neurotoxins should be considered risk factors that may detrimentally interact with predisposing genetic factors. ...
Current diagnostic options for Parkinson’s disease are very limited and primarily based on characteristic clinical symptoms. Thus, there are urgent needs for reliable biomarkers that enable us to diagnose the disease in the early stages, differentiate it from other atypical Parkinsonian syndromes, monitor its progression, increase knowledge of its pathogenesis, and improve the development of potent therapies. A promising group of potential biomarkers are endogenous tetrahydroisoquinoline metabolites, which are thought to contribute to the multifactorial etiology of Parkinson’s disease. The aim of this critical review is to highlight trends and limitations of available traditional and modern analytical techniques for sample pretreatment (extraction and derivatization procedures) and quantitative determination of tetrahydroisoquinoline derivatives in various types of mammalian fluids and tissues (urine, plasma, cerebrospinal fluid, brain tissue, liver tissue). Particular attention is paid to the most sensitive and specific analytical techniques, involving immunochemistry and gas or liquid chromatography coupled with mass spectrometric, fluorescence, or electrochemical detection. The review also includes a discussion of other relevant agents proposed and tested in Parkinson’s disease.
... Reports from Canada, Spain, United States, Italy, and Chile have shown that: (i) the administration of inhibitors of catalase or acetaldehyde trapping agents inhibits alcohol self-administration in animals (Aragon and Amit, 1992;Koechling and Amit, 1994;Tampier et al., 1995;Orrico et al., 2017;Peana et al., 2015); (ii) rats self-administer acetaldehyde into the brain ventral tegmental area (VTA), at concentrations that are three orders of magnitude lower than those required for ethanol to induce its self-administration (Rodd et al., 2005); and (iii) a VTA-directed gene transduction aimed at either inhibiting catalase synthesis or overexpressing the low K m aldehyde dehydrogenase 2 (ALDH2) virtually blocks the self-administration of ethanol (Karahanian et al., 2011(Karahanian et al., , 2015. Additionally, (iv) it has been shown that salsolinol, the adduct formed between acetaldehyde and dopamine, likely mediates the early reinforcing effects of acetaldehyde (Quintanilla et al., 2014;Melis et al., 2015;Quintanilla et al., 2016a;Rodd et al., 2003;Rojkovicova et al., 2008). The reader is referred to a comprehensive review on the actions of acetaldehyde (Correa et al., 2012). ...
Chronic ethanol intake results in brain oxidative stress and neuroinflammation, which have been postulated to perpetuate alcohol intake and to induce alcohol relapse. The present study assessed the mechanisms involved in the inhibition of: (i) oxidative stress; (ii) neuroinflammation; and (iii) ethanol intake that follow the administration of the antioxidant N-acetylcysteine (NAC) and the anti-inflammatory acetylsalicylic acid (ASA) to animals that had consumed ethanol chronically. At doses used clinically, NAC [40 mg/kg per day orally (p.o.)] and ASA (15 mg/kg per day p.o.) significantly inhibited chronic alcohol intake and relapse intake in alcohol-preferring rats. The coadministration of both drugs reduced ethanol intake by 65% to 70%. N-acetylcysteine administration: (a) induced the Nrf2-ARE system, lowering the hippocampal oxidative stress assessed as the ratio of oxidized glutathione (GSSG)/reduced glutathione (GSH); (b) reduced the neuroinflammation assessed by astrocyte and microglial activation by immunofluorescence; and (c) inhibited chronic and relapse ethanol intake. These effects were blocked by sulfasalazine, an inhibitor of the xCT transporter, which incorporates cystine (precursor of GSH) and extrudes extracellular glutamate, an agonist of the inhibitory mGlu2/3 receptor, which lowers the synaptic glutamatergic tone. The inhibitor of mGlu2/3 receptor (LY341495) blocked the NAC-induced inhibition of both relapse ethanol intake and neuroinflammation without affecting the GSSG/GSH ratio. Unlike N-acetylcysteine, ASA inhibited chronic alcohol intake and relapse via lipoxin A4, a strong anti-inflammatory metabolite of arachidonic acid generated following the ASA acetylation of cyclooxygenases. Accordingly, the lipoxin A4 receptor inhibitor, WRW4, blocked the ASA-induced reduction of ethanol intake. Overall, via different mechanisms, NAC and ASA administered in clinically relevant doses combine their effects inhibiting ethanol intake.
... In addition, the condensation product of acetaldehyde and dopamine, salsolinol (Ito et al., 2018), has been found in the fetal brain following chronic prenatal alcohol exposure (Mao et al., 2013). Salsolinol has been shown to be involved in the motivational effects of alcohol and its high intake and produces its effect by interacting with the µ-opioid receptors in the posterior ventral tegmental area (Xie et al., 2012;Quintanilla et al., 2014;Peana et al., 2017), Therefore, the monoamine system appears to be directly implicated in the reinforcing effects of alcohol, and, consequently in prenatal learning about alcohol; although the role of this system has not yet been fully investigated. This could yet prove to be the missing link between the reinforcing action of acetaldehyde and the activation of the opioid system. ...
Prenatal alcohol exposure has been found to be an important factor determining later consumption of this drug. In humans, despite the considerable diversity of variables that might influence alcohol consumption, longitudinal studies show that maternal alcohol intake during gestation is one of the best predictors of later alcohol use from adolescence to young adulthood. Experimental studies with animals also provide abundant evidence of the effects of prenatal alcohol exposure on later alcohol intake. In addition to increased consumption, other effects include enhanced palatability and attractiveness of alcohol flavor as well as sensitization to its sensory and reinforcing effects. Most of these outcomes have been obtained after exposing rats to binge-like administrations of moderate alcohol doses during the last gestational period when the fetus is already capable of detecting flavors in the amniotic fluid and learning associations with aversive or appetitive consequences. On this basis, it has been proposed that one of the mechanisms underlying the increased acceptance of alcohol after its prenatal exposure is the acquisition (by the fetus) of appetitive learning via an association between the sensory properties of alcohol and its reinforcing pharmacological effects. It also appears that this prenatal appetitive learning is mediated by the activation of the opioid system, with fetal brain acetaldehyde playing an important role, possibly as the main chemical responsible for its activation. Here, we review and analyze together the results of all animal studies testing these hypotheses through experimental manipulation of the behavioral and neurochemical elements of the assumed prenatal association. Understanding the mechanisms by which prenatal alcohol exposure favors the early initiation of alcohol consumption, along with its role in the causal pathway to alcohol disorders, may allow us to find strategies to mitigate the behavioral effects of this early experience with the drug. We propose that prenatal alcohol exposure is regarded as a case of involuntary early onset of alcohol use when designing prevention policies. This is particularly important, given the notion that the sooner alcohol intake begins, the greater the possibility of a continued history of alcohol consumption that may lead to the development of alcohol use disorders.
... Most of the experimental data refer to exogenous (RS)-salsolinol hydrochloride applied as a racemic mixture. Quintanilla et al. (2014Quintanilla et al. ( , 2016) not only chirally separated a commercially available (RS)-salsolinol but also purified it from isosalsolinol. Isosalsolinol is a by-product of non-enzymatical Pictet-Spengler condensation, and at physiological pH, the reaction of acetaldehyde and dopamine generates (RS)-salsolinol and isosalsolinol in equal proportions, while under non-physiological in vitro conditions (low pH), the synthesis of (RS)-salsolinol predominates ( Almodovar et al. 2017;Bates et al. 1986;King et al. 1974). ...
Salsolinol (6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline), widely available in many edibles, is considered to alter the function of dopaminergic neurons in the central nervous system and thus, multiple hypotheses on its either physiological and/or pathophysiological role have emerged. The aim of our work was to revisit its potentially neurotoxic and/or neuroprotective role through a series of both in vitro and in vivo experiments. Salsolinol in the concentration range 10–250 μM did not show any significant release of lactate dehydrogenase from necrotic SH-SY5Y cells and was able in the concentration of 50 and 100 μM to rescue SH-SY5Y cells from death induced by H2O2. Its neuroprotective effect against neurotoxin 6-hydroxydopamine was also determined. Salsolinol was found to decrease significantly the reactive oxygen species level in SH-SY5Y cells treated by 500 μM H2O2 and the caspase activity induced by 300 μM of H2O2 or 100 μM of 6-hydroxydopamine. Serum levels of TNFα and CRP of salsolinol-treated rats were not significantly different from control animals. Both TNFα and CRP served as indirect markers of neurotoxicity and/or neuroprotection. Although the neurotoxic properties of salsolinol have numerously been emphasized, its neuroprotective properties should not be neglected and need greater consideration.
... This activation could be mediated by the action of salsolinol over MORs and not by the ethanol molecule itself. In line with recent studies showing that acquisition of ethanol-induced CPP (i.p. or icv) can be prevented by inhibiting MORs (Gajbhiye et al., 2017;Gibula-Bruzda et al., 2015;Quintanilla et al., 2014), we showed here that the blockade of local pVTA MORs during the conditioning phase impaired the acquisition of ethanol place preference. This highlights the key role of the MORs in the VTA in the development of ethanol induced contextlearned associations. ...
... This highlights the key role of the MORs in the VTA in the development of ethanol induced contextlearned associations. Moreover, recent studies have demonstrated that salsolinol is able to act as an agonist of the MORs (Berríos-Cárcamo et al., 2016;Hipólito et al., 2011;Quintanilla et al., 2014;Xie et al., 2012). To our knowledge, there is no evidence in the literature of direct ethanol interaction with the MORs (Melis et al., 2015) although it is clearly stated that MORs antagonists are at some level useful to reduce alcohol compulsive intake (Soyka, 2016). ...
The neurobiological mechanisms underlying alcohol motivational properties are still not fully understood, however, the mu-opioid receptors (MORs) have been evidenced as central elements in the manifestation of the alcohol reinforcing properties. Drug-associated environmental stimuli can trigger alcohol relapse and promote alcohol consumption whereby N-methyl-d-aspartate (NMDA) receptors play a pivotal role. Here we sought to demonstrate, for the first time, that ethanol induces conditioned place preference or aversion (CPP or CPA) when administered locally into the ventral tegmental area (VTA) and the associated role of MORs. We further analyzed the changes in the expression and mRNA levels of GluN1 and GluN2A subunits in designated brain areas. The expression of CPP or CPA was characterized following intra-VTA ethanol administration and we showed that either reinforcing (CPP) or aversive (CPA) properties are dependent on the dose administered (ranging here from 35 to 300 nmol). Furthermore, the critical contribution of local MORs in the acquisition of CPP was revealed by a selective antagonist, namely β-Funaltrexamine. Finally, modifications of the expression of NMDA receptor subunits in the Nucleus Accumbens (NAc) and Hippocampus after ethanol-induced CPP were analyzed at the proteomic and transcriptomic levels by western blot and In Situ Hybridation RNAscope techniques, respectively. Results showed that the mRNA levels of GluN2A but not GluN1 in NAc are higher after ethanol CPP. These novel results pave the way for further characterisation of the mechanisms by which ethanol motivational properties are associated with learned environmental cues.
... Reports from Canada, Spain, United States, Italy, and Chile have shown that: (i) the administration of inhibitors of catalase or acetaldehyde trapping agents inhibits alcohol self-administration in animals (Aragon and Amit, 1992;Koechling and Amit, 1994;Tampier et al., 1995;Orrico et al., 2017;Peana et al., 2015); (ii) rats self-administer acetaldehyde into the brain ventral tegmental area (VTA), at concentrations that are three orders of magnitude lower than those required for ethanol to induce its self-administration (Rodd et al., 2005); and (iii) a VTA-directed gene transduction aimed at either inhibiting catalase synthesis or overexpressing the low K m aldehyde dehydrogenase 2 (ALDH2) virtually blocks the self-administration of ethanol (Karahanian et al., 2011(Karahanian et al., , 2015. Additionally, (iv) it has been shown that salsolinol, the adduct formed between acetaldehyde and dopamine, likely mediates the early reinforcing effects of acetaldehyde (Quintanilla et al., 2014;Melis et al., 2015;Quintanilla et al., 2016a;Rodd et al., 2003;Rojkovicova et al., 2008). The reader is referred to a comprehensive review on the actions of acetaldehyde (Correa et al., 2012). ...
Chronic alcohol intake leads to neuroinflammation and cell injury, proposed to result in alterations that perpetuate alcohol intake and cued relapse. Studies show that brain oxidative stress is consistently associated with alcohol-induced neuroinflammation, and literature implies that oxidative stress and neuroinflammation perpetuate each other. In line with a self-perpetuating mechanism, it is hypothesized that inhibition of either oxidative stress or neuroinflammation could reduce chronic alcohol intake and relapse. The present study conducted on alcohol-preferring rats shows that chronic ethanol intake was inhibited by 50% to 55% by the oral administration of low doses of either the antioxidant N-acetylcysteine (40 mg/kg/d) or the anti-inflammatory aspirin (ASA; 15 mg/kg/d), while the co-administration of both dugs led to a 70% to 75% (P < .001) inhibition of chronic alcohol intake. Following chronic alcohol intake, a prolonged alcohol deprivation, and subsequent alcohol re-access, relapse drinking resulted in blood alcohol levels of 95 to 100 mg/dL in 60 minutes, which were reduced by 60% by either N-acetylcysteine or aspirin and by 85% by the co-administration of both drugs (blood alcohol: 10 to 15 mg/dL; P < .001). Alcohol intake either on the chronic phase or following deprivation and re-access led to a 50% reduction of cortical glutamate transporter GLT-1 levels, while aspirin administration fully returned GLT-1 to normal levels. N-acetylcysteine administration did not alter GLT-1 levels, while N-acetylcysteine may activate the cystine/glutamate transport xCT, presynaptically inhibiting relapse. Overall, the study suggests that a neuroinflammation/oxidative stress self-perpetuation cycle maintains chronic alcohol intake and relapse drinking. The co-administration of anti-inflammatory and antioxidant agents may have translational value in alcohol-use disorders.
... Is there a relationship between salsolinol in the periphery and in the brain with respect to both neurotoxic and neurobehavioural effects? Interestingly, some evidence has shown that salsolinol may reach the brain by crossing the blood-brain barrier (Sjöquist and Magnuson 1980;Quintanilla et al. 2014). Nevertheless, some authors otherwise reported that salsolinol should not be able to cross the bloodbrain barrier because its single peripheral administration did not result in measurable salsolinol levels in the brain (Origitano et al. 1981;Székács et al. 2007). ...
The 1,2,3,4-tetrahydroisoquinolines (TIQs) are compounds frequently described as alkaloids that can be found in the human body fluids and/or tissues including the brain. In most circumstances, TIQs may be originated as a consequence of reactions, known as Pictet-Spengler condensations, between biogenic amines and electrophilic carbonyl compounds, including ethanol’s main metabolite, acetaldehyde. Several TIQs may also be synthesized enzymatically whilst others may be formed in the body as by-products of other compounds including TIQs themselves. The biological actions of TIQs appear critically dependent on their metabolism, and nowadays, among TIQs, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), N-methyl-1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (N-methyl-(R)-salsolinol), 1-[(3,4-dihydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol (norlaudanosoline or tetrahydropapaveroline or THP) and 1-benzyl-1,2,3,4-tetrahydroisoquinoline (1BnTIQ) are considered as those endowed with the most potent neurotoxic actions. However, it remains to be established whether a continuous exposure to TIQs or to their metabolites might carry toxicological consequences in the short- or long-term period. Remarkably, recent findings suggest that some TIQs such as (1-[(4-hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol) (higenamine) and 1-methyl-1,2,3,4-tetrahydroisoquinoline (1-MeTIQ) as well as N-methyl-tetrahydroisoquinoline (N-methyl-TIQ) exert unique neuroprotective and neurorestorative actions. The present review article provides an overview on these aspects of TIQs and summarizes those that presently appear the most significant highlights on this puzzling topic.
... It is involved in the etiology of neurodegenerative disorders such as Parkinson's disease. It can cross the BBB and increase oxidative stress and α-synuclein aggregation via cytochrome C oxidation [32][33][34]. In addition, chronic alcohol use stimulates the production of highly reactive molecules (e.g., reactive oxygen species), leading to oxidative stress [35]. ...
The liver is a key organ that can communicate with many other districts of the human body. In the last few decades, much interest has focused on the interaction between the liver and the gut microbiota, with their reciprocal influence on biosynthesis pathways and the integrity the intestinal epithelial barrier. Dysbiosis or liver disorders lead to0 epithelial barrier dysfunction, altering membrane permeability to toxins. Clinical and experimental evidence shows that the permeability hence the delivery of neurotoxins such as LPS, ammonia and salsolinol contribute to neurological disorders. These findings suggested multi-organ communication between the gut microbiota, the liver and the brain. With a view to in vitro modeling this liver-based multi-organ communication, we describe the latest advanced liver-on-a-chip devices and discuss the need for new organ-on-a-chip platforms for in vitro modeling the in vivo multi-organ connection pathways in physiological and pathological situations.
