Acetaldehyde sequestering prevents ethanol-induced stimulation of mesolimbic dopamine transmission

Enrico, Paolo; Sirca, Donatella; Mereu, Maddalena; Peana, Alessandra Tiziana; Lintas, Alessandra; Golosio, A.; Diana, Marco

doi:10.1016/j.drugalcdep.2008.10.010

Cited by 58 publications

(75 citation statements)

References 33 publications

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“…Many laboratories have tested the role of the ethanol metabolite acetaldehyde, by impairing its formation (see Correa et al, 2011 for review) or using acetaldehyde sequestering agents such as D-penicilamine (Enrico et al, 2009;Martí-Prats et al, 2010;Pautassi et al, 2010). All of these in vivo studies have shown that the behavioral, neurochemical, and electrophysiological properties of ethanol are impaired when acetaldehyde, and conse- quently salsolinol, cannot be formed (Enrico et al, 2009;Martí-Prats et al, 2010). In our experiments, however, neither D-penicilamine nor dopamine depletion reduced the effect of ethanol, suggesting that in slices the excitation of dopamine cells by ethanol may not be mediated by salsolinol.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…The first step of Etoh oxidation generates acetaldehyde (AA), which is toxic, reactive, and potentially carcinogenic. AA is aversive systemically, as has been observed from the unpleasant effects of disulfuram, an inhibitor of AA dehydrogenase, but it has been shown to be rewarding in parts of the brain (12,15,16) especially in the posterior ventral tegmental area (17)(18)(19) by activating dopamine neurons (20)(21)(22). The liver maintains circulating levels of AA at levels of 20-155 μM (23,24), and AA has been reported not to penetrate the blood-brain barrier or to penetrate very slowly (23,25).…”

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confidence: 99%

Oxidation of ethanol in the rat brain and effects associated with chronic ethanol exposure

Wang

Jiang³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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It has been reported that chronic and acute alcohol exposure decreases cerebral glucose metabolism and increases acetate oxidation. However, it remains unknown how much ethanol the living brain can oxidize directly and whether such a process would be affected by alcohol exposure. The questions have implications for reward, oxidative damage, and long-term adaptation to drinking. One group of adult male Sprague-Dawley rats was treated with ethanol vapor and the other given room air. After 3 wk the rats received i.v. [2-13 C]ethanol and [1, 2-13 C 2 ]acetate for 2 h, and then the brain was fixed, removed, and divided into neocortex and subcortical tissues for measurement of 13 C isotopic labeling of glutamate and glutamine by magnetic resonance spectroscopy. Ethanol oxidation was seen to occur both in the cortex and the subcortex. In ethanol-naïve rats, cortical oxidation of ethanol occurred at rates of 0.017 ± 0.002 μmol/min/g in astroglia and 0.014 ± 0.003 μmol/min/g in neurons, and chronic alcohol exposure increased the astroglial ethanol oxidation to 0.028 ± 0.002 μmol/min/g (P = 0.001) with an insignificant effect on neuronal ethanol oxidation. Compared with published rates of overall oxidative metabolism in astroglia and neurons, ethanol provided 12.3 ± 1.4% of cortical astroglial oxidation in ethanol-naïve rats and 20.2 ± 1.5% in ethanol-treated rats. For cortical astroglia and neurons combined, the ethanol oxidation for naïve and treated rats was 3.2 ± 0.3% and 3.8 ± 0.2% of total oxidation, respectively. 13C labeling from subcortical oxidation of ethanol was similar to that seen in cortex but was not affected by chronic ethanol exposure.T he liver is the major organ for the oxidation of ethanol (Etoh) (1, 2), followed by the stomach and other organs. Acetate (Ac) generated from Etoh by the liver is consumed by the brain (3, 4), where it replaces a significant portion of cerebral glucose metabolism in humans and animals (5-8), either decreasing glucose consumption directly or compensating for glucose consumption decreased by some other effect. However, the brain may also oxidize Etoh (9-14), and that capacity is important with respect to several perspectives. The first step of Etoh oxidation generates acetaldehyde (AA), which is toxic, reactive, and potentially carcinogenic. AA is aversive systemically, as has been observed from the unpleasant effects of disulfuram, an inhibitor of AA dehydrogenase, but it has been shown to be rewarding in parts of the brain (12,15,16) especially in the posterior ventral tegmental area (17-19) by activating dopamine neurons (20)(21)(22). The liver maintains circulating levels of AA at levels of 20-155 μM (23, 24), and AA has been reported not to penetrate the blood-brain barrier or to penetrate very slowly (23,25). Thus, if the brain can oxidize Etoh, then intracerebral AA may mediate behavioral, neurochemical, and toxic effects of Etoh in the brain, possibly playing a role in the development of alcohol dependence (6,16,26).AA is difficult to measure in living systems. The ...

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“…As noted earlier, the first product coming from brain-EtOH metabolism by the activity of Compound I is acetaldehyde. Acetaldehyde is a psychoactive molecule that, when administered centrally, exerts a broad range of behavioral (Arizzi-LaFrance et al, 2006;Rodd-Henricks et al, 2002;Smith et al, 1984) and neurochemical (Diana et al, 2008;Enrico et al, 2009;Foddai et al, 2004;Sirca et al, 2011) effects that are similar to those induced by EtOH in rodents. 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.…”

Section: Discussionmentioning

confidence: 99%

“…Various reports have demonstrated that manipulations that reduce the activity of this neurotransmitter system decrease voluntary EtOH intake in rodents (Nguyen et al, 2007;Thanos et al, 2005). Moreover, acetaldehyde has been shown to be capable of stimulating the transmission of mesolimbic Da (Deehan et al, 2013;Deng and Deitrich, 2008;Enrico et al, 2009;Foddai et al, 2004;Sirca et al, 2011). Several authors have proposed that acetaldehyde mediates the EtOH-induced stimulation of mesolimbic Da transmission.…”

Section: Discussionmentioning

confidence: 99%

“…Several authors have proposed that acetaldehyde mediates the EtOH-induced stimulation of mesolimbic Da transmission. It has been reported that both acetaldehyde sequestration with Dpenicillamine and L-cysteine, or the inhibition of brain catalase activity by AT prevent the activation of this brain circuitry evoked by EtOH (Deng and Deitrich, 2008;Enrico et al, 2009;Sirca et al, 2011). Brain catalase has been shown to be highly active in aminergic neurons and along the mesolimbic DA pathway (Deng and Deitrich, 2008;Zimatkin and Lindros, 1996).…”

Section: Discussionmentioning

confidence: 99%

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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

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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Acetaldehyde sequestering prevents ethanol-induced stimulation of mesolimbic dopamine transmission

Cited by 58 publications

References 33 publications

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

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

Oxidation of ethanol in the rat brain and effects associated with chronic ethanol exposure

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

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Acetaldehyde sequestering prevents ethanol-induced stimulation of mesolimbic dopamine transmission

Cited by 58 publications

References 33 publications

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

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

Oxidation of ethanol in the rat brain and effects associated with chronic ethanol exposure

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

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Product

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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