Sequential Changes in Brain Glutamate and Adenosine A1 Receptors May Explain Severity of Adolescent Alcohol Withdrawal after Consumption of High Levels of Alcohol.

Abstract

There is an excellent correlation between the age when alcohol consumption begins and the likelihood of lifelong problems with alcohol abuse. Alcohol use often begins in adolescence, a time marked by brain development and maturation of numerous brain systems. Rats are an important model, wherein the emergence of alcohol withdrawal symptoms serves as a gauge of dependency following chronic alcohol consumption. Previous work has shown that adolescent Long-Evans rats consume high levels of alcohol and develop a severe alcohol withdrawal syndrome when fed alcohol as part of a liquid diet. Acutely, alcohol inhibits two important excitatory receptors for glutamate (NMDA and AMPA) and may further decrease glutamate activity through modulatory adenosine receptors. The present study focuses on potential adaptive changes in expression of these receptors that may create a receptor imbalance during chronic alcohol consumption and lead to severe overexcitation of the adolescent brain during alcohol withdrawal. Levels of brain expression of NMDA, AMPA, and adenosine A1 and A2a receptors were determined by Western blotting after adolescent rats consumed an alcohol-containing liquid diet for 4, 11, or 18 days. Severity of alcohol withdrawal was also assessed at these time points. Levels increased for both AMPA and NMDA receptors, significant and approaching maximal by day 11. In contrast, A1 receptor density showed a slow decline reaching significance at 18 days. There were no changes in expression of adenosine A2a receptor. The most severe withdrawal symptoms appear to coincide with the later downregulation of adenosine A1 receptors coming on top of maximal upregulation of excitatory AMPA and NMDA glutamate receptors. Thus, loss of adenosine "brakes" on glutamate excitation may punctuate receptor imbalance in alcohol-consuming adolescents by allowing the upregulation of the excitatory receptors to have full impact during early alcohol withdrawal.