Norepinephrine turnover and voluntary consumption of ethanol in the rat

Socaransky, S.M.; Aragón, Carlos M.G.; Rusk, Ilene N.; Amit, Zalman; Ögren, Sven Ove

doi:10.1016/0741-8329(85)90071-0

Cited by 8 publications

(4 citation statements)

References 16 publications

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“…Acute ethanol exposure can modulate NE synthesis (Corrodi et al, 1966), increase NE turnover and release (Socaransky et al, 1985), downregulate central alpha-2 (α 2 ) adrenergic receptors (Thiele et al, 2000), prolong NE half-life ( t 1/2 ), and reduce NE circulatory clearance (Eisenhofer et al, 1983). Pharmacological approaches that deplete the NE level (Brown and Amit, 1977) or reduce NE turnover (Socaransky et al, 1985) specifically reduce ethanol consumption in rodents. In the clinical setting, administration of the NE synthesis inhibitor, α-methyl- p -tyrosine (AMPT) in healthy volunteers, has shown biobehavioral effects such as reducing alcohol-induced euphoria and stimulation (Ahlenius et al, 1973).…”

Section: Introductionmentioning

confidence: 99%

“…Although the contribution of NE in mediating reward pathways has been recognized for some time, NE has received little attention as a potential treatment target for alcohol dependence (AD). Acute EtOH exposure can modulate NE synthesis (Corrodi et al, 1966), increase NE turnover and release (Socaransky et al, 1985), down-regulate central alpha-2 (a 2 )-adrenergic receptors (Thiele et al, 2000), prolong NE half-life (t 1/2 ), and reduce NE circulatory clearance (Eisenhofer et al, 1983). Pharmacological approaches that deplete the NE level (Brown and Amit, 1977) or reduce NE turnover (Socaransky et al, 1985) specifically reduce EtOH consumption in rodents.…”

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confidence: 99%

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Effects of Idazoxan on Alcohol Pharmacokinetics and Intoxication: A Preliminary Human Laboratory Study

Haass‐Koffler

Leggio

Davidson

et al. 2015

Alcohol Clin Exp Res

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Background Preliminary basic and human studies suggest that the α2-adrenergic antagonist idazoxan may represent a novel medication for alcohol dependence (AD). The goal of this study was to evaluate the safety and tolerability of the co-administration of idazoxan with alcohol and explore whether pharmacokinetics (PK) and biobehavioral (Pharmacodynamics, PD) mechanisms of idazoxan may alter alcohol's effects. Methods This was a preliminary double-blind, single-dose, placebo-controlled, cross-over, randomized human laboratory study. Ten social drinkers were dosed, in two different alcohol challenge sessions (ACS), with a single oral dose of idazoxan (40-mg) or placebo, followed by a fixed alcohol dose 60 minutes later. Participants returned after a one-week wash-out and they were crossed over to the opposite medication condition. Results There were no significant differences in adverse events (AEs) between idazoxan and placebo. Moreover, during the ACS paradigm, 40-mg idazoxan was well tolerated with no significant autonomic effects compared to placebo; idazoxan reduced the peak blood alcohol level (Cmax) (p<.01) and time to peak (tmax) (p<.05) compared to placebo. A PK/PD model aligned the biobehavioral effects, demonstrating that the co-administration of 40-mg idazoxan with alcohol, decreased alcohol-related stimulation (p<.05) and increased alcohol-related sedation (p<.05). Conclusions This study supports the safety and tolerability of 40-mg idazoxan when co-administered with alcohol. Additionally, this study suggests that idazoxan may alter the biphasic effects of alcohol by decreasing stimulation and increasing sedation. These findings have implications for further investigation of using idazoxan as a probe to develop potential novel medications to treat alcoholic patients.

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Effects of Idazoxan on Alcohol Pharmacokinetics and Intoxication: A Preliminary Human Laboratory Study

Haass‐Koffler

Leggio

Davidson

et al. 2015

Alcohol Clin Exp Res

View full text Add to dashboard Cite

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“…Thus, one α 2 -agonist, lofexidine, has been reported (Lê et al ., 2005) to attenuate stress-induced reinstatement of alcohol-seeking behaviour and to also decrease alcohol self-administration, whereas the opposite effects were induced by the α 2 antagonist yohimbine. Another α 2 agonist, FLA-57, also reduces alcohol consumption (Socaransky et al ., 1985; Daoust et al ., 1990). The brain entry of α-methyldopa formed peripherally from carbidopa could be inhibited through competition by Trp, which shares the same carrier mechanism responsible for the transport of neutral (aromatic and branched-chain) amino acids and also L -dopa itself across the blood-brain barrier (Oldendorf, 1971).…”

Section: Discussionmentioning

confidence: 99%

Tryptophan in Alcoholism Treatment II: Inhibition of the Rat Liver Mitochondrial Low Km Aldehyde Dehydrogenase Activity, Elevation of Blood Acetaldehyde Concentration and Induction of Aversion to Alcohol by Combined Administration of Tryptophan and Benserazide

Badawy

Bano

Steptoe

2011

Alcohol and Alcoholism

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Aims: The aims were to provide proofs of mechanism and principle by establishing the ability of the amino acid L-tryptophan (Trp) combined with the kynureninase inhibitor benserazide (BSZ) to inhibit the liver mitochondrial low Km aldehyde dehydrogenase (ALDH) activity after administration and in vivo and to induce aversion to alcohol. Methods: Trp, BSZ or both were administered to male Wistar rats and ALDH activity was determined both in vitro in liver homogenates and in vivo (by measuring acetaldehyde accumulation in blood after ethanol administration). Alcohol consumption was studied in an aversion model in rats and in alcohol-preferring C57 mice. Results: Combined administration of Trp + BSZ, but neither compound alone, produced a strong inhibition of ALDH activity and an increase in blood acetaldehyde concentration after ethanol, and induced aversion to alcohol in rats and decreased preference in mice. Another kynureninase inhibitor, carbidopa, induced aversion to alcohol by itself, which was reversed by Trp co-administration. Conclusions: The present results establish a prior art for the use of a combination of Trp plus BSZ in the treatment of alcoholism by aversion, which merits rapid clinical development.

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“…Acute alcohol exposure (one injection 2 g/kg as 5% solution i.p.) has been shown to modulate NE synthesis (Corrodi et al, 1966), to increase NE release (Socaransky et al, 1985), and to downregulate central alpha-2 adrenergic receptors (Thiele et al, 2000). Yohimbine, an alpha-2 adrenoceptor antagonist increases NE cell firing and NE release into extracellular fluid (Abercrombie et al, 1988) by blocking pre-synaptic inhibition; yohimbine increases anxiety and has been extensively used as pharmacological stressor.…”

Section: Introductionmentioning

confidence: 99%

Noradrenergic targets for the treatment of alcohol use disorder

2018

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The role of norepinephrine (NE) in the development of alcohol use disorder (AUD) has been studied over the past several decades. However, the NE system has been largely ignored for many years as a potential target for medication development for AUD. More recently, preclinical and clinical studies have demonstrated the potential value of targeting NE signaling for developing new pharmacological treatments for AUD. This review contributes to a special issue of Psychopharmacology focused on promising targets for alcohol addiction. Specifically, this review coalesces preclinical and clinical neuroscience that re-evaluate the noradrenergic system, and in particular the alpha-1 receptor, as a potential target for AUD.

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Norepinephrine turnover and voluntary consumption of ethanol in the rat

Cited by 8 publications

References 16 publications

Effects of Idazoxan on Alcohol Pharmacokinetics and Intoxication: A Preliminary Human Laboratory Study

Effects of Idazoxan on Alcohol Pharmacokinetics and Intoxication: A Preliminary Human Laboratory Study

Tryptophan in Alcoholism Treatment II: Inhibition of the Rat Liver Mitochondrial Low Km Aldehyde Dehydrogenase Activity, Elevation of Blood Acetaldehyde Concentration and Induction of Aversion to Alcohol by Combined Administration of Tryptophan and Benserazide

Noradrenergic targets for the treatment of alcohol use disorder

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