Adenosine is an important neuromodulator of central nervous system (CNS) excitability, and a major inhibitor of synaptic transmission. Enhancement of adenosine mediated processes may explain the sedative actions of a variety of drugs currently used as anticonvulsants, anxiolytics and tranquilizers. Recent observations suggest that adenosine is involved in the expression of some of the CNS effects of ethanol. The objective of this study is to test the hypothesis that some of the acute and chronic effects of ethanol are mediated indirectly through an adenosine receptor system and may account for differences in the expression of initial sensitivity, tolerance, and dependence on ethanol. Genetic hypotheses concerning the relationship between purinergic and ethanol sensitivity will be studied using stocks of mice, Long Sleep (LS) and Short Sleep (SS), bred for differences in initial sensitivity to ethanol. Alteration of adenosine receptors will be achieved by administering either adenosine agonists or antagonists using a continuous infusion method. Following chronic infusion, mice will be tested for sensitivity to ethanol by measuring ethanol sleep time and waking blood and brain ethanol concentrations. in some experiments ethanol will be pulse-infused and withdrawal measured by changes in body temperature and home-cage activity using a Mini-Mitter telemetry system. Following chronic drug treatments and tolerance, cross-tolerance, and dependence testing, alterations in adenosine receptors and receptor coupling mechanisms will be measured by binding and quantitative autoradiographic techniques to examine more specifically the anatomical location and extent of receptor loss or increase. The social and clinical prevalence of alcohol abuse is a major health problem. Recent evidence suggests that drugs which bind to adenosine receptors alter alcohol responding. Although the interaction between alcohol and adenosine receptor systems is highly complex, such studies may provide information useful in determining the mechanisms responsible for differential sensitivity to the effects of ethanol.
