Basal and adenosine receptor-stimulated levels of cAMP are reduced in lymphocytes from alcoholic patients.

Abstract

Alcoholism causes serious neurologic disease that may be due, in part, to the ability of ethanol to interact with neural cell membranes and change neuronal function. Adenosine receptors are membrane-bound proteins that appear to mediate some of the effects of ethanol in the brain. Human lymphocytes also have adenosine receptors, and their activation causes increases in cAMP levels. To test the hypothesis that basal and adenosine receptor-stimulated cAMP levels in lymphocytes might be abnormal in alcoholism, we studied lymphocytes from 10 alcoholic subjects, 10 age-and sexmatched normal individuals, and 10 patients with nonalcoholic liver disease. Basal and adenosine receptor-stimulated cAMP levels were reduced 75% in lymphocytes from alcoholic subjects. Also, there was a 76% reduction in ethanol stimulation of cAMP accumulation in lymphocytes from alcoholics. Similar results were demonstrable in isolated T cells. Unlike other laboratory tests examined, these measurements appeared to distinguish alcoholics from normal subjects and from patients with nonalcoholic liver disease. Reduced basal and adenosine receptor-stimulated levels of cAMP in lymphocytes from alcoholics may reflect a change in cell membranes due either to chronic alcohol abuse or to a genetic predisposition unique to alcoholic subjects.Despite the widespread incidence of alcoholism, the molecular events accounting for intoxication, tolerance, and physical dependence after alcohol abuse are poorly understood. Ethanol is believed to intercalate into cell membranes, producing acute and adaptive changes in membrane fluidity (1, 2) or membrane constituents (3,4). Adenosine receptors are membrane-bound proteins that appear to mediate some of the effects of ethanol in the central nervous system (5). We recently reported (6) that ethanol acutely increases adenosine receptor-stimulated cAMP levels in a clonal neural cell line (neuroblastoma-glioma hybrid and that with time these cells adapt to the presence of ethanol, showing a reduction in adenosine receptor-stimulated cAMP levels. After chronic exposure to ethanol, the NG108-15 cells require ethanol to achieve normal levels of adenosine receptorstimulated cAMP, which may indicate a form of cellular "dependence." This process is completely reversible upon ethanol withdrawal.These observations suggest that intact single cells adapt to the presence of ethanol. Moreover, depressed adenosine receptor-stimulated cAMP levels in cells might be a biochemical change of pathophysiologic significance in chronic alcoholism. Since human lymphocytes have the same A2 adenosine receptors as the neuroblastoma cells (7), we could test directly whether alcoholics have altered cAMP levels. We undertook a controlled study of basal and adenosine receptor-stimulated cAMP levels in lymphocytes of chronic alcoholics, normal subjects, and patients with nonalcoholic liver disease. Mixed lymphocytes and T cells from chronic alcoholics showed a striking reduction in basal and adenosine receptor-stimulated cAMP levels. Moreov...

Differential expression of guanosine triphosphate binding proteins in men at high and low risk for the future development of alcoholism.

“…Several lines of evidence indicate that alcoholic individuals have abnormal adenylyl cyclase signal transduction and that genetic determinants may account for some of these differences. Stimulated cAMP production in freshly isolated platelets and lymphocytes is reduced in alcoholics compared to nonalcoholic controls (11,12). Moreover, after multiple generations in culture, lymphocytes from alcoholics not only recover their responsiveness but develop enhanced sensitivity to factors that stimulate cAMP (13).…”

cAMP-dependent Protein Kinase Types I and II Differentially Regulate cAMP Response Element-mediated Gene Expression

“…Cell Culture-NG108-15 neuroblastoma ϫ glioma hybrid cells obtained from the cell culture facility at the University of California (San Francisco) were grown in 10% Serum Plus (JRH Biosciences) at 37°C in a 10% CO 2 incubator as described previously (12). All cells were maintained for 3 days in complete defined medium (13).…”

Peri-operative Decreased cAMP Levels in Long-term Alcoholic Patients

“…After chronic ethanol exposure, these cells require ethanol to reach normal levels of adenosine receptor-stimulated cAMP, which may indicate a form of cellular dependence. 23,24 Lymphocytes from chronic alcoholic patients exhibited reduced basal and reduced stimulated cAMP levels and increased resistance to ethanol stimulation of adenosine receptor-dependent cAMP accumulation. 23,25 Recent studies have focused on adenylyl cyclase, which is activated via receptor-modulated G-protein and generates cAMP.…”