GANGLIOSIDES REDUCE THE DEVELOPMENT OF ETHANOL DEPENDENCE WITHOUT AFFECTING ETHANOL TOLERANCE

Mice given an ethanol-containing liquid diet, as their sole source of nutrients and fluid, rapidly developed functional tolerance to and phy sical dependence on ethanol. The presence of physical dependence was d emonstrated by measured signs of central nervous system hyperexcitabil ity upon withdrawal of ethanol. The withdrawal hyperexcitability, whic h included tremors, handling-induced seizures and spontaneous clonic/t onic seizures, was more pronounced when mice consumed the ethanol-cont aining diet for 7 days, compared with 5 days. Daily treatment of the a nimals with either a ganglioside mixture (extracted bovine brain gangl iosides, 250 or 500 mg/kg i.p.) or ganglioside GM1 (100 mg/kg i.p.) fo r the terminal two-thirds of the ethanol administration period resulte d in a significant reduction in the ethanol withdrawal signs. On the o ther hand, tolerance to the hypnotic action of ethanol, tested 30 hr a fter withdrawal of ethanol, was unaffected by ganglioside treatment. G anglioside GM1 given i.c.v. at a daily dose of 10 mu g during the etha nol ingestion period was as effective as 100 mg/kg GM1 given i.p. in r educing signs of ethanol withdrawal. The daily administration of gangl iosides during the feeding of the ethanol diet did not alter the anima ls' ethanol consumption, intoxication or blood ethanol levels at the t ime of ethanol withdrawal. A single dose of GM1 given either i.p. or i .c.v. 16 hr before withdrawal produced no effect on the measured ethan ol withdrawal signs. Our prior work and the work of others has demonst rated a relationship between up-regulation of N-methyl-D-aspartate rec eptor numbers in brain and the manifestation of ethanol withdrawal sig ns. Daily administration of GMI, during the last 5 days of a 7-day per iod of ethanol ingestion, prevented the up-regulation of N-methyl-D-as partate receptors in the hippocampus and reduced the ethanol withdrawa l signs. Our data demonstrate that the daily administration of ganglio sides during the period of ethanol consumption may prevent the develop ment of ethanol physical dependence, while leaving ethanol tolerance i ntact.