Aspirin and N‐acetylcysteine co‐administration markedly inhibit chronic ethanol intake and block relapse binge drinking: Role of neuroinflammation‐oxidative stress self‐perpetuation

Abstract

Chronic alcohol intake leads to neuroinflammation and cell injury, proposed to result in alterations that perpetuate alcohol intake and cued-relapse. Studies show that brain oxidative stress is consistently associated with alcohol-induced neuroinflammation, and literature implies that oxidative stress and neuroinflammation perpetuate each other. In line with a self-perpetuating mechanism, it is hypothesized that inhibition of either oxidative stress or neuroinflammation could reduce chronic alcohol intake and relapse. The present study conducted on alcohol-preferring rats shows that chronic ethanol intake was inhibited by 50-55% by the oral administration of low doses of either the antioxidant N-acetyl cysteine (40 mg/kg/day) or the anti-inflammatory aspirin (ASA; 15 mg/kg/day), while the co-administration of both dugs led to a 70-75% (p<0.001) inhibition of chronic alcohol ntake. Following chronic alcohol intake, a prolonged alcohol deprivation and subsequent alcohol reaccess, relapse-drinking resulted in blood-alcohol levels of 95-100 mg/dl in 60 minutes which were reduced by 60% by either N-acetyl cysteine or aspirin, and by 85% by the co-administration of both drugs (blood-alcohol: 10-15 mg/dl; p<0.001). Alcohol intake either on the chronic phase or following deprivation and re-access led to a 50% reduction of cortical glutamate transporter GLT-1 levels, while aspirin administration fully returned GLT-1 to normal levels. N-acetyl cysteine administration did not alter GLT-1 levels, while N-acetyl cysteine may activate the cystine/glutamate transport xCT, presynaptically inhibiting relapse. Overall, the study suggests that a neuroinflammation/oxidative stress self-perpetuation cycle maintains chronic alcohol intake and relapse drinking. The coadministration of anti-inflammatory and antioxidant agents may have translational value in alcoholuse-disorders.