Change of cystine/glutamate antiporter expression in ethanol-dependent rats

Abstract

Background: Some drugs of abuse down regulate the expression of cystine/glutamate (xCT) antiporter in the nucleus accumbens (Acb) after extinction or withdrawal. The altered level of xCT exchanger in Acb, a structure involved in ethanol reinforcement, may contribute to the pathological glutamatergic signaling, linked to addiction. We hypothesized that the expression of xCT may be changed in Acb and whole brain also in non-dependent (occasional drinkers), ethanol-dependent rats, as well as, during ethanol withdrawal.Methods: Wistar rats were made ethanol-dependent by chronic exposure to an alcoholic milk beverage (from 2.4 to 7.2% v/v ethanol). Ethanol non-dependent rats were exposed to a similar, but non-alcoholic liquid diet and self-administered ethanol (10%) twice a week. Withdrawal in ethanol-dependent rats was studied at 12 h after the last ethanol-enriched diet exposure. Immediately after the measurement of somatic signs of withdrawal, Western blot analysis with a polyclonal antibody against xCT was carried out in a naïve control group, non-dependent and ethanol-dependent rats as well as withdrawal rats, in order to study the level of xCT expression in Acb and whole brain.Results: Non-dependent rats self-administered an average dose of 1.21 ± 0.02 g/kg per session (30 min). Daily ethanol consumption during chronic exposure to the alcoholic beverage ranged from 6.30 ± 0.16 to 13.99 ± 0.66 g/kg. Ethanol dependent rats after suspension of the ethanol-enriched diet have shown significant somatic signs of withdrawal. Western blotting analysis of Acb lysates revealed that xCT was over expressed in ethanol-dependent rats whereas in whole brain preparations xCT was over expressed in both non-dependent and ethanol-dependent rats compared to control group. On the contrary, xCT expression during withdrawal was down regulated in Acb and restored to control level in whole brain preparations.Conclusions: The changes of xCT expression in both Acb and whole brain following ethanol dependence and withdrawal indicate that xCT might represent a novel therapeutic target for the treatment of ethanol addiction.

Beyond the “First Hit”: Marked Inhibition byN-Acetyl Cysteine of Chronic Ethanol Intake But Not of Early Ethanol Intake. Parallel Effects on Ethanol-Induced Saccharin Motivation

“…Peana and colleagues () showed marked increases of the cystine/glutamate exchanger in nucleus accumbens of rats under forced chronic EtOH intake (reaching EtOH intakes of 6 to 14 g/EtOH/kg/d, in line with the voluntary intakes of rats in the present study). Such an increase in the cystine/glutamate exchanger may constitute a compensatory mechanism, although not efficient under normal or low cystine levels, to lower extracellular glutamate levels to normal.…”

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“…Apparently, prolonged periods of ethanol exposure are necessary to elicit changes in xCT expression. Some authors have found decreased levels of xCT expression after at least three weeks of chronic ethanol exposure (Alhaddad et al, 2014;Peana et al, 2014). In our study, we did not find alterations in xCT content, probably due to our relatively short period (less than two weeks) of ethanol exposure.…”

From Ethanol to Salsolinol: Role of Ethanol Metabolites in the Effects of Ethanol

“…94,95 However, the peripheral administration of l-cysteine or N-acetyl cysteine during maintenance could potentiate the cystine/ glutamate exchanger level, which might restore extracellular glutamate levels to normal. 87,93 However, the idea that acetaldehyde might be responsible for the first hit is in contrast with other studies revealing that a negative interference with catalase-H 2 O 2 metabolic pathway has been shown to impair the maintenance and further phases of oral ethanol self-administration 43 as well as of voluntary ethanol intake. 83 It is possible that the interference with catalase-H 2 O 2 operated by a-lipoic acid (a-LA), in this study, could be a stronger mechanism, more capable to reduce central (and peripheral) acetaldehyde production.…”

“…In this regard, we have recently shown a marked increase in the expression of the cystine/ glutamate exchanger in the nucleus accumbens of ethanol dependent rats that, under chronic ethanol taking, reach on average 6-14 g/kg/day of ethanol intake. 93 Such an increase in the cystine/glutamate exchanger has been interpreted to represent a compensatory mechanism, although not efficient under normal or low cystine levels, to reduce extracellular glutamate levels to normal. In fact, rats that consume high ethanol levels show marked increases in extracellular glutamate.…”