Enkephalinase inhibition: Regulation of ethanol intake in genetically predisposed mice

Blum, Kenneth; Briggs, Arthur H.; Trachtenberg, Michael C.; DeLallo, L; Wallace, Jack E.

doi:10.1016/0741-8329(87)90084-x

Cited by 85 publications

(46 citation statements)

References 49 publications

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“…Although the C57 mouse is sometimes described as "alcohol preferring" or even "alcohol seeking" (18), in fact its intake of alcohol is contingent on the availability of other food and fluids (19)(20)(21). The distinction is of some practical consequence.…”

Section: Discussionmentioning

confidence: 99%

Toward an analogue of alcoholism in mice: analysis of nongenetic variance in consumption of alcohol.

Dole¹,

A²,

Gentry³

1988

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

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Drinking behavior of the isogenic mouse strain C57BL/6J was analyzed into nongenetic components: stochastic fluctuations, responses to fluctuations in the current environment, and persistent differences between individual animals. The latter accounted for the major part of the variance. The variance was neither increased by differences in diet during the postweaning rapid growth period (prior to assay for drinking choice) nor diminished by uniformity of treatment during this period, suggesting that significant differentiation had occurred prior to weaning. The large variance between animals could be explained by assuming that the genetic role in consumption of alcohol by C57BL mice is permissive-a relative insensitivity to the aversive orosensory and pharmacological effects of 10% alcohol-rather than a specific drug-seeking predisposition.Mice of the inbred C57BL strain differ significantly in consumption of alcohol, even under carefully controlled conditions (1, 2). They also differ in other behavioral traits such as fighting capacity, emotionality, and susceptibility to audiogenic seizures despite having essentially the same genome (3). There is thus an interesting contrast between genetic identity and behavioral diversity, a phenomenon that must stem from differential effects of the environment (4).In the present study, this isogenic strain was used to analyze the variance of drinking behavior into three components: stochastic fluctuations (transient variations in consumption of alcohol, uncorrelated between animals), responses to concurrent stimuli (shown by correlated variations in a replicate group), and persistent differences between animals in the same environment (found when the daily consumption of each animal is averaged over several weeks). The latter differences point to an effect of earlier experiences, not necessarily involving alcohol, and are the principal concern of this report. If genetically heterogeneous animals living under apparently identical conditions exhibited as great a variance in drinking behavior as that of the C57BL mice, it would be natural to attribute their variance to genetic diversity and to use the differences in their drinking as guides to selective breeding. With such animals, selective breeding will segregate only the genetic contribution. Previous work in our laboratory has dealt mainly with the immediate effects of diet or drugs on consumption of alcohol by C57BL/6J mice (5-8). For these purposes, a preliminary stratification of animals into groups was made after a period of baseline observation to ensure similar group averages before treatment. These experiments therefore always involved a substantial within-group variance of alcohol consumption. The present study examines the source of this pretreatment variance.In principle, a persistent bias toward or against alcohola substance with both nutrient and pharmacological actions-could be established by experiences at any time after conception. The problem is to identify the epochs in development when the animal's...

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Section: Discussionmentioning

confidence: 99%

Toward an analogue of alcoholism in mice: analysis of nongenetic variance in consumption of alcohol.

Dole¹,

A²,

Gentry³

1988

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

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“…These enzymes could play a crucial role in the motivation to drink alcohol, as well as in the development and maintenance of alcohol consumption, as suggested by other authors (Blum et al 1987;George et al 1991;Szczepanska et al 1996a, b;Siems et al 2000). Enkephalins are mainly hydrolyzed by four peptidase activities in the brain: 1) the aminopeptidase N (EC 3.4.17.3,APN), which cleaves the Tyr 1 -Gly 2 amide bond; 2) the membrane-dipeptidase A (EC 3.4.13.11), which hydrolyzes the Gly 2 -Gly 3 bond; 3) the angiotensinconverting enzyme (EC 3.4.15.1,ACE), and 4) the neutral endopeptidase (EC 3.4.24.11, NEP, also called enkephalinase or neprilysin), which cleave the Gly 3 -Phe 4 bond (NEP affinity for Met-enk being 1000 times higher than that of ACE) (Schwartz et al 1981).…”

Section: Introductionmentioning

confidence: 83%

“…administration of hydrocinnamic acid and D-phenylalanine (i.p. ), known enkephalinase inhibitors, also raises Met-enk levels in the whole brain of C57BL/6J mice and decreases alcohol consumption (Blum et al 1987). On the other hand, the use of NEP gene knockout mice (NEP −/− KO) has been helpful in investigating the role of this enzyme in alcohol drinking behavior.…”

Section: Introductionmentioning

confidence: 98%

Activity and Expression of Enkephalinase and Aminopeptidase N in Regions of the Mesocorticolimbic System are Selectively Modified by Acute Ethanol Administration

et al. 2011

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Opioid peptides play a key role in ethanol reinforcement and alcohol drinking behavior. However, regulation of opioid levels by peptidase-degrading activities in ethanol's actions in brain is still unclear. The aim of this work was to study the acute effects of ethanol (2.5 g/kg) on enkephalinase (NEP) and aminopeptidase N (APN) activities and expression in regions of the mesocorticolimbic system, as well as on corticosterone levels in serum for up to 24 h after administration. Enzymatic activities were measured by fluorometric assays, mRNA's expression by reverse transcriptase polymerase chain reaction (RT-PCR) and corticosterone levels by radioimmunoassay. Acute ethanol administration modified peptidase activity and expression with different kinetics. Ethanol induced a transitory increase and decrease in NEP and APN activities in the frontal cortex (FC) and ventral tegmental area (VTA), whereas only increases in these activities were observed in the nucleus accumbens (NAcc). Ethanol induced an increase in NEP mRNA in the FC and decreases in APN mRNA in the FC and NAcc. In contrast, ethanol produced biphasic effects on both enzymes expression in the VTA. Corticosterone levels were not changed by ethanol. Our results suggest that NEP and APN could play a main role in ethanol reinforcement through regulation of opioid levels in mesolimbic areas.

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“…Since it is not easy to fight the hard wiring of our brain reward circuitry, for the recovering addict it seems obvious to look for reward outside of our genome [i.e. alcohol, drugs, sex, and food] [180][181][182][183][184][185][186].…”

Section: Second-restore Us To Sanitymentioning

confidence: 99%

Epigenetic Changes Induced by Exercise

Archer¹

2015

J Reward Defic Syndr

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Enkephalinase inhibition: Regulation of ethanol intake in genetically predisposed mice

Cited by 85 publications

References 49 publications

Toward an analogue of alcoholism in mice: analysis of nongenetic variance in consumption of alcohol.

Toward an analogue of alcoholism in mice: analysis of nongenetic variance in consumption of alcohol.

Activity and Expression of Enkephalinase and Aminopeptidase N in Regions of the Mesocorticolimbic System are Selectively Modified by Acute Ethanol Administration

Epigenetic Changes Induced by Exercise

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