Prevention of Ethanol‐Induced Behavioral Stimulation by d‐Penicillamine: A Sequestration Agent for Acetaldehyde

Font, Laura; Miquel, Marta; Aragón, Carlos M.G.

doi:10.1097/01.alc.0000171945.30494.af

Cited by 52 publications

(57 citation statements)

References 61 publications

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“…For this reason, it has been proposed that brain-EtOH-derived acetaldehyde could play a role in some of the psychopharmacological effects caused by EtOH. In agreement to this, it has been observed that administration of acetaldehyde chelating agents, such as D-penicillamine and L-cysteine, prevents a wide range of EtOH-elicited behaviors, including EtOH intake (Font et al, 2005(Font et al, , 2006Mart ı-Prats et al, 2010;Pautassi et al, 2010;Peana et al, 2010). The results obtained in this study indicated that H 2 O 2 levels are critical to EtOH intake.…”

Section: Discussionsupporting

confidence: 87%

Reduction in Central H₂O₂Levels Prevents Voluntary Ethanol Intake in Mice: A Role for the Brain Catalase-H₂O₂System in Alcohol Binge Drinking

Ledesma

Baliño

Aragón

2013

Alcohol Clin Exp Res

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Background: Hydrogen peroxide (H 2 O 2 ) is the cosubstrate used by the enzyme catalase to form Compound I (the catalase-H 2 O 2 system), which is the major pathway for the conversion of ethanol (EtOH) into acetaldehyde in the brain. This centrally formed acetaldehyde has been shown to be involved in some of the psychopharmacological effects induced by EtOH in rodents, including voluntary alcohol intake. It has been observed that different levels of this enzyme in the central nervous system (CNS) result in variations in the amount of EtOH consumed. This has been interpreted to mean that the brain catalase-H 2 O 2 system, by determining EtOH metabolism, mediates alcohol self-administration. To date, however, the role of H 2 O 2 in voluntary EtOH drinking has not been investigated.Methods: In the present study, we explored the consequence of a reduction in cerebral H 2 O 2 levels in volitional EtOH ingestion. With this end in mind, we injected mice of the C57BL/6J strain intraperitoneally with the H 2 O 2 scavengers alpha-lipoic acid (LA; 0 to 50 mg/kg) or ebselen (Ebs; 0 to 25 mg/kg) 15 or 60 minutes, respectively, prior to offering them an EtOH (10%) solution following a drinkingin-the-dark procedure. The same procedure was followed to assess the selectivity of these compounds in altering EtOH intake by presenting mice with a (0.1%) solution of saccharin. In addition, we indirectly tested the ability of LA and Ebs to reduce brain H 2 O 2 availability.Results: The results showed that both LA and Ebs dose-dependently reduced voluntary EtOH intake, without altering saccharin consumption. Moreover, we demonstrated that these treatments decreased the central H 2 O 2 levels available to catalase.Conclusions: Therefore, we propose that the amount of H 2 O 2 present in the CNS, by determining brain acetaldehyde formation by the catalase-H 2 O 2 system, could be a factor that determines an animal's propensity to consume EtOH.

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Section: Discussionsupporting

confidence: 87%

Reduction in Central H₂O₂Levels Prevents Voluntary Ethanol Intake in Mice: A Role for the Brain Catalase-H₂O₂System in Alcohol Binge Drinking

Ledesma

Baliño

Aragón

2013

Alcohol Clin Exp Res

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“…In six cells, 86 mM ethanol significantly increased firing by 56 Ϯ 21% (n ϭ 6; p Ͻ 0.01), which was not significantly different (p ϭ 0.65) from the effect of ethanol seen without pretreatment in reserpine (44 Ϯ 6%; n ϭ 5). We also applied ethanol to midbrain slices pretreated with D-penicillamine, a highly selective agent for sequestering acetaldehyde in vivo (Font et al, 2005). Brain slices were pretreated for Ͼ90 min with D-penicillamine (10 mM in ACSF).…”

Section: Does Salsolinol Mediate Ethanol's Excitatory Action In Slices?mentioning

confidence: 99%

Salsolinol Stimulates Dopamine Neurons in Slices of Posterior Ventral Tegmental Area Indirectly by Activating μ-Opioid Receptors

Xie

Hipólito²,

Zuo³

et al. 2011

J Pharmacol Exp Ther

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Previous studies in vivo have shown that salsolinol, the condensation product of acetaldehyde and dopamine, has properties that may contribute to alcohol abuse. Although opioid receptors, especially the -opioid receptors (MORs), may be involved, the cellular mechanisms mediating the effects of salsolinol have not been fully explored. In the current study, we used whole-cell patch-clamp recordings to examine the effects of salsolinol on dopamine neurons of the ventral tegmental area (VTA) in acute brain slices from Sprague-Dawley rats. Salsolinol (0.01-1 M) dose-dependently and reversibly increased the ongoing firing of dopamine neurons; this effect was blocked by naltrexone, an antagonist of MORs, and gabazine, an antagonist of GABA A receptors. We further showed that salsolinol reduced the frequency without altering the amplitude of spontaneous GABA A receptor-mediated inhibitory postsynaptic currents in dopamine neurons. The salsolinol-induced reduction was blocked by both naltrexone and [D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin, an agonist of MORs. Thus, salsolinol excites VTA-dopamine neurons indirectly by activating MORs, which inhibit GABA neurons in the VTA. This form of disinhibition seems to be a novel mechanism underlying the effects of salsolinol.

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“…Studies using D-penicillamine have established that sequestering ACD results in a reduction of alcohol intake and a decrease in alcohol conditioned place preference in rats Font et al, 2006b;Peana et al, 2008). D-penicillamine also reduces alcohol conditioned place preference and alcohol induced motor depression in mice (Font et al, 2005;Font et al, 2006a).…”

Section: Alcohol Acetaldehyde and Acetaldehyde Productsmentioning

confidence: 99%

“…Research has shown that both central and peripheral administration of ACD cause an increase in alcohol consumption in rats (Brown et al, 1979;. Rats will exhibit ACD induced CPP and stimulus preference suggesting that ACD is rewarding (Quertemont & De Witte, 2001;Quintanilla & Tampier, 2003;Smith et al, 1984;Spina et al, 2010); blocking or sequestering the formation of ACD resulting from alcohol exposure produces alterations in the neurobiological and behavioral effects of alcohol (Aragon & Amit, 1992;Diana et al, 2008;Font et al, 2005;Font et al, 2006a;Font et al, 2006b;Kaharanian et al, 2011;Koechling & Amit, 1994;Peana et al, 2008). While it is currently difficult to assert that ACD is absolutely necessary for the neurobiological and behavioral actions of alcohol, data show that ACD is likely to be involved to some extent.…”

Section: Acetaldehyde Is Pharmacologically Active In the Cnsmentioning

confidence: 99%

What is in that Drink: The Biological Actions of Ethanol, Acetaldehyde, and Salsolinol

Deehan

Brodie

Rodd

2011

Behavioral Neurobiology of Alcohol Addiction

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Alcohol abuse and alcoholism represent substantial problems that affect a large portion of individuals throughout the world. Extensive research continues to be conducted in an effort to identify the biological basis of the reinforcing properties of alcohol in order to develop effective pharmacotherapeutic and behavioral interventions. One theory that has developed within the alcohol field over the past 4 decades postulates that the reinforcing properties of alcohol are due to the action of the metabolites/products of alcohol within the central nervous system (CNS). The most extreme version of this theory suggests that the biologically active metabolites/products of alcohol, created from the breakdown from alcohol, are the ultimate source of the reinforcing properties of alcohol. The contrary theory proposes that the reinforcing properties of alcohol are mediated completely through the interaction of the ethanol molecule with several neurochemical systems within the CNS. While there are scientific findings that offer support for both of these stances, the reinforcing properties of alcohol are most likely generated through a complex series of peripheral and central effects of both alcohol and its metabolites. Nonetheless, the development of a greater understanding for how the metabolites/products of alcohol contribute to the reinforcing properties of alcohol is an important factor in the development of efficacious pharmacotherapies for alcohol abuse and alcoholism. This chapter is intended to provide a historical perspective of the role of acetaldehyde (the first metabolite of alcohol) in alcohol reinforcement as well as review the basic research literature on the effects of acetaldehyde (and acetaldehyde metabolites/products) within the CNS and how these function with regard to alcohol reward.

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Prevention of Ethanol‐Induced Behavioral Stimulation by d‐Penicillamine: A Sequestration Agent for Acetaldehyde

Cited by 52 publications

References 61 publications

Reduction in Central H₂O₂Levels Prevents Voluntary Ethanol Intake in Mice: A Role for the Brain Catalase-H₂O₂System in Alcohol Binge Drinking

Reduction in Central H₂O₂Levels Prevents Voluntary Ethanol Intake in Mice: A Role for the Brain Catalase-H₂O₂System in Alcohol Binge Drinking

Salsolinol Stimulates Dopamine Neurons in Slices of Posterior Ventral Tegmental Area Indirectly by Activating μ-Opioid Receptors

What is in that Drink: The Biological Actions of Ethanol, Acetaldehyde, and Salsolinol

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Prevention of Ethanol‐Induced Behavioral Stimulation by d‐Penicillamine: A Sequestration Agent for Acetaldehyde

Cited by 52 publications

References 61 publications

Reduction in Central H2O2Levels Prevents Voluntary Ethanol Intake in Mice: A Role for the Brain Catalase-H2O2System in Alcohol Binge Drinking

Reduction in Central H2O2Levels Prevents Voluntary Ethanol Intake in Mice: A Role for the Brain Catalase-H2O2System in Alcohol Binge Drinking

Salsolinol Stimulates Dopamine Neurons in Slices of Posterior Ventral Tegmental Area Indirectly by Activating μ-Opioid Receptors

What is in that Drink: The Biological Actions of Ethanol, Acetaldehyde, and Salsolinol

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Reduction in Central H₂O₂Levels Prevents Voluntary Ethanol Intake in Mice: A Role for the Brain Catalase-H₂O₂System in Alcohol Binge Drinking

Reduction in Central H₂O₂Levels Prevents Voluntary Ethanol Intake in Mice: A Role for the Brain Catalase-H₂O₂System in Alcohol Binge Drinking