Journal of Neuroscience Research 24:391-397 (1989) zy Developmental Profile Synthetase in Lines of Ethanol Sensitivity of Glutamine Mice Bred for N. Sakellaridis, D. Mangoura, J.M. Masserrano, V. Detsis, C.J. Leoni, zyxw R. Deitrich, and A. Vernadakis Departments of Psychiatry (N.S., D.M., A.V.) and Pharmacology (N.S., D.M., J.M.M., V.D., C.J.L., R.D., A.V.), University of Colorado School of Medicine, Denver Glutamine synthetase (GS) activity was used as a marker to examine differences in astrocyte develop- ment in mice selectively bred for ethanol sensitivity: long sleep (LS), short sleep (SS), mild ethanol with- drawal (MEW), severe ethanol withdrawal (SEW) and control ethanol withdrawal (CEW). We found that 1) GS activity in MEW and SEW was higher than in LS and SS during the first zyxwvu 2 weeks of post- natal development, in the forebrain but not in the cerebellum; 2) lower GS activity was observed con- sistently in all areas examined with the SS mice as compared to the LS; 3) glutamine synthetase activity in MEW and SEW differed significantly from their controls (CEW) during the early developmental pe- riod regardless of the brain region examined; how- ever, after 30 days of maturation, GS activity in SEW was higher than that in MEW and CEW in the fore- brain. Astrocytes are known to contribute in the reg- ulation of the neuronal microenvironment. There- fore, we interpret the differences we found in astrocytic function during early brain development among these lines of mice to account in part for the neuronal predisposition to ethanol sensitivity. Key words: astrocytes, glia, brain development, long sleep, short sleep mice (IBG), mied ethanol with- drawal mice (IBG), severe ethanol withdrawal (IBG) INTRODUCTION Genetically bred lines of mice have been estab- lished as a model to study ethanol sensitivity dependence and withdrawal. Mice bred genetically for the difference in duration for the loss of the righting reflex after an acute dose of ethanol have been designated as “long sleep” (LS) and “short sleep” (SS) (McClearn and Kahi- kana, 1973, 1981). It has been determined that the dif- ference in acute behavioral sensitivity to ethanol in the LS and SS mice is not a result of differences in activity of hepatic alcohol dehydrogenase, aldehyde dehydroge- nase, the microsomal ethanol oxidizing system, or the elimination of ethanol from central venous blood (Heston et al., 1974; French et al., 1979; Howerton et al., 1983), rather it is attributed to central nervous system sensitiv- ity. Another set of lines of mice has been developed by the Institute of Behavioral Genetics in Boulder, Colo- rado, in an attempt to produce a genetic animal model by selecting for severity of the withdrawal syndrome. They used a battery of symptoms, including the occurrence of seizures on handling (Goldstein, 1972) and loss of body temperature control (Tabakoff and Ritzman, 1979) as criteria. These replicate new lines were named SEW for severe ethanol withdrawal, MEW for mild ethanol with- drawal, and CEW for control (Wilson et al., 1984). Hoffer and associates (Sorensen et al., 1980, 1981) have found that cerebellar Purkinje neurons from LS mice were one to two orders of magnitude more sensitive to the depressant effects of locally administered ethanol than those from the SS mice. The alterations were found to be brain region-specific and depressant drug-specific rather than generalized. Although, undoubtedly, neuronal sensitivity has a very strong genetic component, epigenetic influences cannot be excluded. A profound epigenetic influence on expression of neuronal sensitivity could be originating from glia cells. There is abundant evidence that glial cells regulate numerous functions of the nervous system (see references in “Astrocytes,” Fedoroff and Vern- Received January 16, 1989; revised July 14, 1989; accepted July 17, 1989. This work was reported in part at the 14th Meeting of the Society for Neuroscience (Sakellaridis et al., 1988). Dr. N. Sakellaridis’s present address is Department of Pharmacology and Toxicology, University of Indiana School of Medicine, Northwest Center for Medical Education, 3400 Broadway, Gary IN 46408. Ad- dress reprint requests to him there. Dr. D. Mangoura’s present address is Departments of Pediatrics, Bio- chemistry, and Molecular Biology, University of Chicago Medical School, 5841 South Maryland Avenue, Chicago, IL 60637. zy 0 1989 Alan R. Liss, Inc.