Ethanol-Dependent Synthesis of Salsolinol in the Posterior Ventral Tegmental Area as Key Mechanism of Ethanol’s Action on Mesolimbic Dopamine

Frontiers in Neuroscience, Journal Year: 2021, Volume and Issue: 15

Published: June 28, 2021

Abnormal consumption of ethanol, the ingredient responsible for alcoholic drinks’ addictive liability, causes millions deaths yearly. Ethanol’s potential is triggered through activation, by a still unknown mechanism, mesolimbic dopamine (DA) system, part key motivation circuit, DA neurons in posterior ventral tegmental area (pVTA) projecting to ipsilateral nucleus accumbens shell (AcbSh). The present vivo brain microdialysis study, dually-implanted rats with one probe pVTA and another or contralateral AcbSh, demonstrates this mechanism. As consequence oral administration pharmacologically relevant dose we simultaneously detect a) pVTA, substance, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), untraceable under control conditions, product condensation between ethanol’s first by-product, acetaldehyde; b) significant increase release. Moreover, such newly generated salsolinol increasing AcbSh release via μ opioid receptor (μOR) stimulation. In fact, inhibition salsolinol’s generation blockade μORs prevents ethanol-increased ipsilateral, but not contralateral, This evidence discloses long-sought mechanism suggests grounds developing preventive therapeutic strategies against abnormal consumption.

Language: Английский

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N-Acetylcysteine and Acetylsalicylic Acid Inhibit Alcohol Consumption by Different Mechanisms: Combined Protection

Frontiers in Behavioral Neuroscience, Journal Year: 2020, Volume and Issue: 14

Published: July 31, 2020

Chronic ethanol intake results in brain oxidative stress and neuroinflammation, which have been postulated to perpetuate alcohol induce relapse. The present study assessed the mechanisms involved inhibition of (i) stress; (ii) neuroinflammation (iii) intake, that follow administration antioxidant N-acetylcysteine anti-inflammatory aspirin (acetylsalicylic acid) animals had consumed chronically. At doses used clinically, (40 mg/kg/day p.o.) (15 p.o) significantly inhibited chronic relapse preferring rats. Co-administration both drugs synergically reduced by 65-70%. suppressed (a) hippocampal as ratio oxidized glutathione (GSSG)/reduced (GSH); (b) astrocyte microglial activation immunofluorescence (c) intake. These effects were blocked sulfasalazine, an inhibitor xCT transporter, incorporates intracellular cystine (precursor GSH) extrudes glutamate, agonist inhibitory mGLU2/3 receptor, lowers glutamatergic tone. receptor (LY 341495) also N-acetylcysteine-induced without affecting GSSH/GSH ratio. Unlike N-acetylcysteine, via lipoxin A4, a strong metabolite arachidonic acid generated following acetylation cyclooxygenases. Accordingly, lipoxinA4 WRW(4) aspirin-induced reduction Overall, shows different Aspirin synergize each other, allowing their low for treatment use disorders.

Language: Английский

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Activation of mitochondrial aldehyde dehydrogenase (ALDH2) by ALDA-1 reduces both the acquisition and maintenance of ethanol intake in rats: A dual mechanism?

Neuropharmacology, Journal Year: 2018, Volume and Issue: 146, P. 175 - 183

Published: Dec. 4, 2018

Language: Английский

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Behavioral consequences of the downstream products of ethanol metabolism involved in alcohol use disorder

Neuroscience & Biobehavioral Reviews, Journal Year: 2021, Volume and Issue: 133, P. 104501 - 104501

Published: Dec. 20, 2021

Language: Английский

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Alcohol as Prodrug of Salsolinol

Springer eBooks, Journal Year: 2022, Volume and Issue: unknown, P. 1 - 24

Published: Jan. 1, 2022

Language: Английский

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Role of Metabolism on Alcohol Preference, Addiction, and Treatment

Current topics in behavioral neurosciences, Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 1, 2023

Language: Английский

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Neurobiological Aspects of Ethanol-Derived Salsolinol

Elsevier eBooks, Journal Year: 2019, Volume and Issue: unknown, P. 227 - 235

Published: Jan. 1, 2019

Language: Английский

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The Central Benzodiazepine Receptor

Oxford University Press eBooks, Journal Year: 2020, Volume and Issue: unknown, P. 68 - 80

Published: Oct. 1, 2020

Abstract Benzodiazepines have been used clinically now for more than a half century the management of anxiety and other conditions. Despite their widespread use, only are mechanisms action pharmacologic implications, especially with long-term beginning to be appreciated. In central nervous system, benzodiazepines act on an allosteric site GABAA receptor enhance activity this inhibitory neurotransmitter. The GABA consists 5 subunits, which can vary among 19 different subtypes, resulting in large number possible configurations receptor. Subunit structure affect binding alter nature interaction between benzodiazepine site, levels activation enhancement. Moreover, distribution these subtypes within varying efficacy, mean that differential effects sites brain. Consequently, may design novel drugs favor particular subunit thus produce profiles. Drugs acting at agonists, enhancing GABA; antagonists, blocking effect site; or inverse producing antipodal agonists.

Language: Английский

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A dual mechanism fully blocks ethanol relapse: Role of vagal innervation

Addiction Biology, Journal Year: 2022, Volume and Issue: 27(2)

Published: Jan. 20, 2022

Abstract Previous studies showed that vagotomy markedly inhibits alcohol self‐administration. Present hypothesised significantly adds to the inhibition of relapse induced by drugs reduce alcohol‐induced hyperglutamatergic state (e.g., N‐acetylcysteine + acetylsalicylic acid). The paradigm tested gauges elevated intake observed in animals had consumed ethanol chronically, were subjected a prolonged deprivation and are subsequently allowed re‐access. Ethanol‐drinker rats (UChB) exposed 10% 20% water concurrently for 4 months, deprived 14 days thereafter re‐access solutions. An initial binge‐like drinking episode is upon re‐access, followed protracted exceeds predeprivation baseline. Prior (i) administered (40 mg/kg/day) acid (15 mg/kg/day), (ii) bilaterally vagotomised, (iii) both treatments or (iv) received no treatments. after repeated deprivations/re‐access cycles inhibited 50%–70% administration 40%–70% vagotomy, while combined plus treatment >95% ( p < 0.001), disclosing dual mechanism subsequent beyond either alone. Future exploration into which vagal activity contributes may have translational promise.

Language: Английский

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Alcohol as Prodrug of Salsolinol

Springer eBooks, Journal Year: 2022, Volume and Issue: unknown, P. 983 - 1005

Published: Jan. 1, 2022

Language: Английский

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