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.

Adenosine A2AReceptors in Substance Use Disorders: A Focus on Cocaine

“…Acute or prolonged ethanol exposure and short- or long-term drug withdrawal did not change the A 2A R numbers and function values in the striatum in mice and rats [ 124 , 135 , 136 , 137 , 138 , 139 , 140 ]. Further, long-term voluntary alcohol drinking did not alter gene expression of the accumbal or striatal A 2A Rs, but significantly increased the number of PLA blots identifying A 2A -D 2 heteroreceptor complexes in the accumbal shell and the dorsal striatum in Wistar rats [ 141 ].…”

Regulation of Synaptic Development by Astrocyte Signaling Factors and Their Emerging Roles in Substance Abuse

“…This disruption would then provide a mechanism for synaptic dysfunction with drugs of abuse, since excess glutamate neurotransmitters are removed from the synapse via astrocyte specific Na+-dependent glutamate transporters, GLT-1 and GLAST [78,79]. Should the tripartite synapse not be properly assembled or maintained, the resulting increased proximal distance of the astrocytic processes to synapses may allow excess glutamate to accumulate and contribute to neuronal hyperexcitability, a hallmark of alcohol and substance abuse [80]. These studies further stress the importance of studying not only the effects of substances of abuse on the neuroligin-neurexin interaction but also the effects on astrocyte-secreted neuroligins more specifically.…”

The Role of the Adenosine System on Emotional and Cognitive Disturbances Induced by Ethanol Binge Drinking in the Immature Brain and the Beneficial Effects of Caffeine

“…Overactivity of the adenosinergic system has been linked to emotional changes in adolescents following withdrawal from high alcohol consumption that persists until adulthood [39]. Therefore, in this review, we explored the ability of caffeine, a nonselective adenosine receptor antagonist, to attenuate or counteract the deleterious effects of ethanol, considering that caffeine affords neuroprotection in different models of neurotoxicity [40,41], attenuating several symptoms of ethanol intoxication such as fatigue, headache, dizziness, weakness, and others [42].…”