Adenosine is recognized as an important neuromodulator of central nervous system (CNS) excitability. Substantial evidence suggests that adenosine is a major inhibitor of synaptic transmission and that 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 may be involved in the expression of some of the CNS effects of ethanol. Thus the objective of this study is to test the hypothesis that differences in the number or affinity of receptors which bind to adenosine account for some of the differences in initial sensitivity or tolerance to ethanol. The animal model to be used in these studies consists of two genetic stocks of mice, the Long Sleep (LS) and Short Sleep (SS) mice, selectively bred for differences in initial sensitivity or tolerance to ethanol. The proposed research will test the hypothesis that alterations of adenosine receptor number or affinity affects the expression of acute sensitivity to ethanol. Alterations of adenosine receptors will be achieved by administering agonists (e.g. cyclohexyladenosine, Lphenylisopropyladenosine, or N- ethylcarboxamidoadenosine) over a period of time using a continuous infusion method. Following chronic infusion LS and SS mice will be tested for their acute sensitivity to ethanol by measuring ethanolinduced hypothermia and ethanol sleep time coupled with measurements of waking blood and brain ethanol concentration. Conversely, cross-tolerance to purinergic drugs will be investigated following chronic infusion of ethanol. Upon completion of the chronic drug treatments and tolerance testing, adenosine receptors will be measured using assays which make use of specific radiolabeled probes to differentiate receptor subtypes. The social and clinical prevalence of alcohol abuse continues to be a major health problem. Studies concerned with the interaction between ethanol and brain receptor systems may provide additional information which will be useful in determining the mechanisms responsible for differential sensitivity to the effects of ethanol.
