Neurobiological Aspects of Ethanol-Derived Salsolinol

C H A P T E R

24 Neurobiological Aspects of Ethanol-Derived Salsolinol Elio Acquas1, Simona Scheggi2 and Alessandra T. Peana3 1

Department of Life and Environmental Sciences, Centre of Excellence on Neurobiology of Addiction, University of Cagliari, Cagliari, Italy 2Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy 3 Department of Chemistry and Pharmacy, University of Sassari, Sassari, Italy

LIST OF ABBREVIATIONS α-MpT AcbSh ACD ADH ALDH CPP DA DMDHIQ1 ERK EtOH GABA H2O2 6-OHDA MPTP NM-SALS N-MT pVTA ROS SALS TIQs

α-methyl-p-tyrosine shell of the nucleus accumbens acetaldehyde alcohol dehydrogenase aldehyde dehydrogenase conditioned place preference dopamine 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion extracellular signal-regulated kinase ethanol γ amino-butyric acid hydrogen peroxide 6-hydroxydopamine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine N-methyl-salsolinol N-methyl-transferases posterior ventral tegmental area reactive oxygen species salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4tetrahydroisoquinoline) tetrahydroisoquinolines

INTRODUCTION Ethanol (EtOH) is still a puzzling psychoactive molecule since its mechanism of action, in spite of the enormous research efforts, remains elusive in many of its pharmacological and toxicological aspects. Indeed, although the complexity of EtOH actions in the central nervous system may be ascribed to its property to directly involve neurotransmitters, such as glutamate (Tabakoff & Hoffman, 2013) and γ amino-butyric acid

Neuroscience of Alcohol. DOI: https://doi.org/10.1016/B978-0-12-813125-1.00024-6

(GABA) (Tabakoff & Hoffman, 2013), a large body of literature strongly supports an indirect participation of dopamine (DA) (So¨derpalm & Ericson, 2013), opioid peptides (Font, Luja´n, & Pastor, 2013), adenosine (Lo´pez-Cruz, Salamone, & Correa, 2013), and serotonin (5-HT) (Vengeliene, Bilbao, Molander, & Spanagel, 2008) to interpret EtOH’s effects on behavior, cognition, motor coordination, and sleep. Moreover, in addition to the involvement of such neurotransmitters, EtOH’s metabolism has also been attributed a critical role on at least two main features: (1) the effects of its main metabolite, acetaldehyde (ACD), being a highly reactive electrophilic compound, and (2) the effects of tetrahydroisoquinolines (TIQs), the condensation products of ACD with nucleophilic molecules (monoamines). In the past few decades, great attention has been placed on peripheral EtOH’s biotransformation by the action of alcohol dehydrogenase (ADH), peroxisomal catalase-hydrogen peroxide (H2O2), cytochrome P450, isoform CYP2E1, and, centrally, by the action of catalase-H2O2-mediated oxidation. Further, aldehyde dehydrogenase (ALDH)-mediated conversion of ACD into acetate also represents a critical factor for the demonstration of the role of EtOH metabolism’s effects. Originating from the observation that a blockade of ACD metabolic disposal, by the use of an ALDH inhibitor (Antabuse, Disulfiram), could cause pleasurable effects in the presence of low doses of EtOH (Chevens, 1953). These investigations revealed that ACD shares with its parent compound a number of psychopharmacological effects. In vivo experiments in this regard

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24. NEUROBIOLOGICAL ASPECTS OF ETHANOL-DERIVED SALSOLINOL

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revealed that the oxidative metabolism of EtOH was prevented by the use of ADH (Peana et al., 2008), catalase-H2O2 (Aragon & Amit, 1985), and ALDH (Zimatkin, Pronko, Vasiliou, Gonzalez, & Deitrich, 2006) inhibitors. Accordingly, the role of ACD in the reinforcing and motivational effects of EtOH was studied upon manipulation of its peripheral and central metabolism and upon application of ACDsequestering agents able to reduce ACD bioavailability (Orrico et al., 2017). In particular, these properties of EtOH-derived ACD (and of ACD on its own) were assessed by place conditioning (Font, Miquel, & Aragon, 2008; Quintanilla & Tampier, 2011) and selfadministration studies (Martı´-Prats, Zornoza, Lo´pezMoreno, Granero, & Polache, 2015; Peana et al., 2011, 2012, 2015; Peana, Muggironi, & Diana, 2010; Peana, Pintus, et al., 2017; Plescia, Brancato, Marino, & Cannizzaro, 2013). Interestingly, further advances have also linked the ability of ADH inhibitors, such as 4methylpyrazole, to indirectly affect catalase-H2O2mediated central EtOH metabolism by interfering with fatty acid oxidation-mediated generation of H2O2 (Peana, Pintus, et al., 2017) (Fig. 24.1). In addition, the critical role of metabolism in the psychopharmacological effects of EtOH has been explained on molecular, cellular, and electrophysiological grounds. In particular, based on the observations that EtOH increases the firing pattern of ventral tegmental area (VTA) DA neurons (Gessa, Muntoni, Collu, Vargiu, & Mereu, 1985), preferentially increases DA transmission (Howard, Schier, Wetzel, Duvauchelle, & Gonzales, 2008) and extracellular signal-regulated kinase (ERK) phosphorylation (Ibba et al., 2009) in the accumbens shell (AcbSh), these studies disclosed the role of EtOHderived ACD in the ability of EtOH to regulate the electrophysiological properties of DA neurons in posterior VTA (pVTA) (Foddai, Dosia, Spiga, & Diana, 2004; Melis, Carboni, Caboni, & Acquas, 2015; Melis, Enrico, Peana, & Diana, 2007; Xie et al., 2012) and, in the AcbSh, DA transmission (Melis et al., 2007) and ERK phosphorylation (Vinci et al., 2010). Moreover, inspired by the demonstration that naltrexone (μ opioid receptor antagonist) prevents the intravenous selfadministration of ACD (Myers, Ng, & Singer, 1984) and by the involvement of central opioidergic system in the effects of EtOH (Font et al., 2013), opioid receptors were shown to exert a crucial influence on the effects of EtOH-derived ACD on locomotor activity (Sa´nchez-Catala´n, Hipo´lito, Zornoza, Polache, & Granero, 2009) and conditioned place preference (CPP) (Pastor & Aragon, 2008) on DA transmission (Melis et al., 2007) and ERK phosphorylation in the AcbSh and on ACD oral self-administration (Peana et al., 2011). These studies, having undergone extensive reviews (Correa et al., 2012; Peana, Sa´nchez-Catala´n,

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FIGURE 24.1 Effect of pVTA 4-methylpyrazole on ethanol self-administration. Effects of intra-pVTA 4-Methylpyrazole (mM in 0.5 μL/min) during maintenance of ethanol self-administration on (A) active responses and (B) ethanol intake (g/kg). Source: Reproduced with permission from Peana, A. T., Pintus, F. A., Bennardini, F., Rocchitta, G., Bazzu, G., Serra, P. A. . . . Acquas, E. (2017). Is catalase involved in the effects of systemic and pVTA administration of 4-methylpyrazole on ethanol self-administration? Alcohol (Fayetteville, N.Y.), Alcohol, 63, 61 73, with minor modifications.

et al., 2017; Peana, Rosas, Porru, & Acquas, 2016), strongly support the tenet that ACD is a pharmacologically active compound on its own and, as EtOH’s metabolite, thus assigning to its metabolism a fundamental role in the mechanism of its psychopharmacological effects. As to the second feature, that is, the role of TIQs and, in particular, of salsolinol (SALS, (R,S)-1-methyl6,7-dihydroxyisoquinoline) in the effects of EtOH, ACD not only directly exerts its known effects but also generates biologically active by-products. Among these molecules, SALS, the condensation product of ACD and DA (Fig. 24.2), has been involved in the neurobiological basis of alcoholism (Davis & Walsh, 1970; Yamanaka, Walsh, & Davis, 1970) and in the neurotoxic consequences of EtOH exposure (Mravec, 2006; Naoi, Maruyama, Akao, & Yi, 2002). The next sections will focus on three significant aspects of the effects of SALS and EtOH-derived SALS: (1) the origin(s) of

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THE ORIGIN OF SALS AND ITS BASAL CONCENTRATIONS IN THE BODY FLUIDS AND IN THE BRAIN

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Synthetic pathways of salsolinol. Salsolinol (bio)synthesis via (A) Pictet-Spengler condensation between dopamine and acetaldehyde or (C) via the postulated salsolinol synthase. Pathway B depicts the condensation between dopamine and pyruvate to yield salsolinol-1-carboxylic acid (still undetermined whether spontaneous (to yield a racemate) or enzymatic). This intermediate undergoes (E1 ) spontaneous decarboxylation into salsolinol or (D) oxidation into 1,2-dehydroxysalsolinol which, in turn, is reduced to salsolinol.

SALS and its basal concentrations in body fluids and the brain; (2) the role of SALS in the neurobiological basis of alcoholism; and (3) the role of SALS in the emergence of neurological disorders associated, in particular, to DA neurodegeneration. Two further issues should be mentioned. The first refers to the advancement on blood and brain ACD determinations since it represents one of the main sources of EtOH-derived SALS. Notably, due to its reactivity, it is very difficult to reliably detect ACD’s concentrations (Correa et al., 2012; Peana, Pintus, et al., 2017); moreover, its spontaneous Pictet-Spengler condensation with nucleophilic amines may take place even after collecting the samples for analysis. All this notwithstanding, and although the in vivo determination of ACD concentrations has long represented a puzzling issue (see Correa et al., 2012), recent data report that ACD can be reproducibly detected in biological fluids and in the brain (Jamal et al., 2016; Schlatter, Chiadmi, Gandon, & Chariot, 2014; Yokoi et al., 2015). The other critical feature to keep in mind is that SALS has a chiral carbon and, therefore, the racemate can be resolved in R-SALS and S-SALS (Fig. 24.2), carrying key metabolic and pharmacodynamic implications.

THE ORIGIN OF SALS AND ITS BASAL CONCENTRATIONS IN THE BODY FLUIDS AND IN THE BRAIN With the above caveats in mind, a critical overview of the literature on the presence of SALS in biological fluids and the brain reveals that, since its discovery in 1970 (Davis & Walsh, 1970), SALS has been detected in very low concentrations both spontaneously and under EtOH ingestion-stimulated conditions. These data, summarized in an excellent review (Hipo´lito, Sa´nchezCatala´n, Martı´-Prats, Granero, & Polache, 2012), reveal that such low concentrations, ranging from picograms/mg (Myers et al., 1985) and picomoles/g (Matsubara, Fukushima, & Fukui, 1987) to nanograms/mg (Haber, Stender, Mangholz, Ehrenreich, & Melzig, 1999) found in rat (Matsubara et al., 1987; Starkey, Mechref, Muzikar, McBride, & Novotny, 2006) and human (DeCuypere, Lu, Miller, & LeDoux, 2008) brain tissue, may depend on a number of factors, including amount, route, and length of EtOH intake (Hipo´lito et al., 2012) as well as SALS’s possible direct ingestion through diet. In agreement with such complexity, Collins, Ung-Chhun, Cheng, and Pronger (1990) reported that in SALS- and L-DOPA- (a DA precursor) free diet fed rats, either short-term (3 weeks) or

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long-term (23 weeks) exposure to an EtOH-containing liquid diet (6.6%, vol/vol) resulted in failure to increase SALS levels in plasma and in different brain regions; however, striatal concentrations of SALS were significantly higher when EtOH intake was supplemented with dietary L-DOPA. Moreover, with respect to SALS’s concentrations in the brain following its systemic intake/administration, the confirmation that SALS crosses the blood brain barrier (BBB) and, hence, that its presence in the brain may not necessarily originate from ACD’s in situ biosynthesis (via lipid peroxidation) has been critical. This issue (Origitano, Hannigan, & Collins, 1981), justified by the observation that SALS has a polarity and a permeability coefficient that would not sustain an easy penetrability through the BBB, was unquestionably set by the demonstration that peripherally-administered SALS could, similarly to centrally-administered SALS (Hipo´lito, Martı´-Prats, Sa´nchez-Catala´n, Polache, & Granero, 2011), elicit CPP and locomotor activity (Matsuzawa, Suzuki, & Misawa, 2000; Quintanilla et al., 2014; Quintanilla et al., 2016). As shown in Fig. 24.2, both SALS’s stereoisomers may originate from the spontaneous condensation between DA and, endogenous or exogenous, ACD. However, since R-SALS is consistently found at higher concentrations than S-SALS (Hipo´lito et al., 2012), it was suggested that R-SALS could be produced enzymatically by the never unequivocally demonstrated (R)-salsolinol synthase (Naoi et al., 1996). In fact, although its isolation was claimed (Naoi et al., 1996), no sequence has been reported for this enzyme, making it impossible to know whether it is, indeed, a genuine (R)-salsolinol synthase or whether (R)-SALS is a by-product of another enzyme. Moreover, bioinformatics analysis has failed, to date, to detect a mammalian sequence homolog to well-known plant PictetSpenglerases (strictosidine and norcoclaurine synthases) able to catalyze the synthesis of distinct TIQs (Ilari et al., 2009). Interestingly, an alternative biochemical pathway of stereo-selective synthesis of SALS has also been suggested through pyruvate (Fig. 24.2) that would condensate, spontaneously or enzymatically, with DA to yield salsolinol-1-carboxylic acid that, in turn, would undergo a spontaneous nonenzymatic decarboxylation to yield SALS.

THE ROLE OF SALS IN THE NEUROBIOLOGICAL BASIS OF ALCOHOLISM Over the past few decades, the role of SALS in the neurobiological basis of alcoholism (Davis & Walsh, 1970; Yamanaka et al., 1970) has long bewildered

neuroscientists up to the more recent demonstrations that involve SALS in the acute, motor stimulant, reinforcing, and motivational effects of EtOH (Correa et al., 2012; Deehan, Brodie, & Rodd, 2013; Hipo´lito et al., 2012; Peana et al., 2016) and that it even facilitates (in alcohol-preferring rats) EtOH consumption (Quintanilla et al., 2016). Accordingly, (R,S)-SALS, at significantly lower concentrations than EtOH, sustains acquisition and maintenance of its intra-pVTA selfadministration (Rodd et al., 2008) and, when delivered in the pVTA, stimulates DA transmission in the Acb (Deehan et al., 2013), locomotor activity (Hipo´lito, Sa´nchez-Catala´n, Zornoza, Polache, & Granero, 2010), and CPP (Hipo´lito et al., 2011). Moreover, the mechanistic relationship between EtOH and its by-products, ACD and SALS, has been demonstrated in pVTA DA neurons (Melis et al., 2015). Using mesencephalic slices from mice treated with α-methyl-p-tyrosine (α-MpT) or reserpine (agents that inhibit DA synthesis and deplete vesicular stores), this elegant investigation demonstrated that SALS, in contrast to ACD and EtOH, stimulates the spontaneous firing of DA neurons even in the absence of newly synthesized DA (Fig. 24.3). However, failure of EtOH or ACD to elicit increased firing activity in DA-depleted animals could be restored by the stoichiometric addition of DA disclosing that, in order to stimulate spontaneous firing of these neurons, EtOH needs to be converted into ACD which, in turn, in the presence of exogenous or endogenous DA (Fig. 24.4), condensates with it to form SALS, the chemical responsible for the observed effects. Interestingly, although this evidence was provided using R,S-SALS, a subsequent study disclosed the role of R-SALS: using an optimal analytical procedure to obtain a chiral separation of the stereoisomers, Quintanilla et al. (2016) demonstrated that the effects of (R,S)-SALS on locomotor activity, CPP and bingelike EtOH intake were reproduced by the administration of R-SALS, but not S-SALS.

THE ROLE OF SALS IN THE EMERGENCE OF NEUROLOGICAL DISORDERS Whatever its source or origin in the brain, SALS’s fate appears linked to the sequential actions of the enzymes N-methyl-transferase (N-MT) to yield Nmethyl-SALS (NM-SALS), and of a semicarbazidesensitive (but not monoamine oxidase-sensitive, MAO) oxidase to yield 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion (DMDHIQ1) (Fig. 24.5) (Maruyama, StrolinBenedetti, & Naoi, 2000; Naoi et al., 2002). DMDHIQ1 may also originate from N-MT by auto-oxidation (Naoi et al., 2002). These metabolic pathways and the large

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FIGURE 24.3 Effects of ethanol, acetaldehyde, and salsolinol on pVTA DA neuronal excitability. Effects of ethanol (100 mM): (A) acetaldehyde (10 nM); (B) salsolinol (100 nM); and (C) on firing rate of pVTA dopamine neurons of mice pretreated with either αMpT (white circles) or reserpine (gray circles). Black bars indicate time of drug application. Gray areas represent mean responses in control mice. Source: Reproduced with permission from Melis, M., Carboni, E., Caboni, P., & Acquas E. (2015). Key role of salsolinol in ethanol actions on dopamine neuronal activity of the posterior ventral tegmental area. Addiction Biology, 20, 182 193, with minor modifications.

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FIGURE 24.4 Effects of ethanol, acetaldehyde, and salsolinol on pVTA DA neuronal excitability: The role of exogenous dopamine. The effect of ethanol (100 mM) on firing rate of pVTA dopamine neurons of αMpT pretreated mice is restored in the presence of exogenous dopamine (10 nM), (A) but is abolished in the presence of DA (10 nM) when acetaldehyde formation is prevented by the catalase H2O2 inhibitor, 3-AT (1 mM) (B). Gray areas represent mean responses in control mice. Source: Reproduced with permission from Melis, M., Carboni, E., Caboni, P., & Acquas E. (2015). Key role of salsolinol in ethanol actions on dopamine neuronal activity of the posterior ventral tegmental area. Addiction Biology, 20, 182 193, with minor modifications.

molecular and mechanistic similarities of these byproducts with the most famous neurotoxins such as 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) (Herraiz, 2016; Mravec, 2006) prompted to the suggestion that SALS might also be involved in the etiopathogenesis of Parkinsonism (Antkiewicz-Michaluk, 2002). In support

of this possibility, experimental evidence indicates that NM-SALS and DMDHIQ1, whose concentrations in the substantia nigra positively correlate with the activity of N-MT in the striatum (Naoi, Maruyama, Matsubara, & Hashizume, 1997), are responsible of dopaminergic cell death through mitochondrial dysfunction mediated by impairment of complex I

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and metabolites in L-DOPA treated patients with respect to healthy controls (Scholz, Klingemann, & Moser, 2004) and since SALS and its by-products were found elevated in the brain and cerebral spinal fluid of patients regardless of their exposure to L-DOPA (Moser et al., 1995), it was concluded that just their central concentrations might serve as a biological marker of the disease (Scholz et al., 2004). Interestingly, although these hypotheses, at least in terms of ethanol-derived SALS, have never reached momentum after their early formulation nor have been supported by epidemiological evidence linking heavy alcohol drinking to EtOH-derived SALS-mediated development of Parkinsonism, a study reporting the effects of H2O2 exposure onto differentiated Parkin knock down PC12 cells disclosed a critical role of SALS and NM-SALS in their oxidative, stress-related, increased vulnerability (Su et al., 2013).

MINI-DICTIONARY OF TERMS

FIGURE 24.5 Metabolic fate of salsolinol. Pathways of NMethyl-salsolinol and of 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion biosynthesis via N-Methylation (A) and (auto-)oxidation (B).

activity, inhibition of electron transport chain, depletion of ATP, and increased production of reactive oxygen species (ROS), as assessed in cell cultures with dopaminergic neuroblastoma SH-SY5Y cells (Kim et al., 2001). Moreover, the involvement of SALS in the basis of Parkinsonism was also sustained by the clinical evidence of increased N-MT activity in Parkinsonians’ lymphocytes (Maruyama et al., 2000; Naoi et al., 2002) and by the cerebrospinal fluid and urine SALS and NM-SALS concentrations (Maruyama, Abe, Tohgi, Dostert, & Naoi, 1996; Niwa et al., 1991) that in the late 1990s brought the suggestion that these molecules could represent a biological marker for early diagnosis and indirect monitoring of the progression of this neurological disorder and of the success of therapeutic approaches (Moser, Scholz, & Nobbe, 1995). These hypotheses were, however, questioned on the grounds of failure to detect SALS and related compounds during early development of the disease in untreated patients and by the observation that therapeutically administered L-DOPA might represent a confounding in their determination. Moreover since there was no correlation between the severity of the disease progression and the concentrations of SALS

Electrophilic Able to accept an electron pair; highly reactive with electron-rich molecules. Nucleophilic Able to donate an electron pair; highly reactive with electron-poor molecules. Pro-drug/Pro-toxic agent Molecule that owes its effects to its metabolic conversion into different biologically active molecules. Racemate Mixture that has equal amounts of left- and right-handed enantiomers of a chiral molecule. Stereoisomer Molecule made of the same atoms connected in the same sequence, but with some of the atoms positioned differently in space with respect to the opposite stereoisomer. Chiral separation Process of separation of two stereoisomers from their racemate.

KEY FACTS Role of Ethanol Metabolism • Ethanol is a psychopharmacologically active compound of extreme pharmacological and toxicological interest. • The exact(s) mechanism(s) of ethanol’s actions are still to be determined. Extensive experimental evidence suggests that it acts through the involvement of multiple neurotransmitter systems and, after its metabolism, into biologically active byproducts, acetaldehyde and salsolinol (the condensation product between acetaldehyde with dopamine). • Ethanol can be considered the pro-drug of the following biologically active molecules: acetaldehyde, salsolinol, N-methyl-salsolinol, and 1,2-dimethyl-6,7-dihydroxyisoquinolinium ion.

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REFERENCES

Role of Stereo-Selectivity in the Effects of Salsolinol • Both R- and S-salsolinol are detected in body fluids and the brain of ethanol-naı¨ve rats and humans, and after ethanol ingestion. • The effects of salsolinol on locomotion, place conditioning, and ethanol intake, originally shown using the racemate, have been demonstrated to be due to R-salsolinol.

Neurotoxicity of Salsolinol By-products • Salsolinol, by the sequential actions of N-methyltransferase and of a semicarbazide-sensitive oxidase is converted into N-methyl-salsolinol and 1,2dimethyl-6,7-dihydroxyisoquinolinium ion, which are toxic to dopaminergic neurons.

SUMMARY POINTS 1. Ethanol acts through glutamate and GABA, but indirectly necessitates dopamine, opioid peptides, adenosine, and serotonin neurotransmission. 2. Ethanol acts through the involvement of ethanolderived acetaldehyde. 3. Acetaldehyde is a highly reactive, electrophilic molecule. 4. Tetrahydroisoquinolines are the acetaldehyde’s condensation products with biogenic monoamines. 5. Salsolinol, the condensation product of acetaldehyde and dopamine, has been implicated in the neurobiological basis of alcoholism and in the emergence of neurological disorders. 6. Ethanol may act both as a pro-drug and a pro-toxic agent.

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