Alcohol. Vol. 8. p~. 39--41.b PergamonPress pie, 1991. Printedin the U.S.A.
0741-8329/91 $3.00 + .00
Body Temperature Influences Ethanol and Ethanol/Pentobarbital Lethality in Mice D E B O R A H A. F I N N , P E T E R J. S Y A P I N , I M A R I N A B E J A N I A N , B R E N D A L. JONES A N D R O N A L D L. A L K A N A 2
Alcohol and Brain Research Laboratory, School of Pharmacy University of Southern California, Los Angeles, CA 90033 Received 30 May 1990; Accepted 15 A u g u s t 1990
FINN, D. A., P. J. SYAPIN, M. 13EJANIAN, B. L. JONES AND R. L. ALKANA. Body temperature influences ethanol and ethanol/pentobarbital lethality in mice. ALCOHOL 8(1) 39-41, 1991.--The effect of body temperature on ethanol (ETOH) or ethanol plus pentobarbital (ETOI-I/PB) lethality was investigated in C57BI./6J mice. Decreasing ambient temperatures from 35-20°C~ decreased rectal temperatures from 38-200C and increased 8-hour survival from 0-93% for ETOH-treated and from 0-100% for ETOH/PB-treated mice. ETOH and ETOH/PB animals with no hypothermia (body temperatures= 38"C) had the highest lethality. Those with body temperatures between 30-32"C had the highest 24-hour survival. These results suggest that conu'olled hypothermia may be useful in reducing lethality from ethanol or ethanol/combination overdoses. Body temperature
Lethality
Ethanol
Pentobarbital
Mice
METHOD
MANIPULATION of body temperature during intoxication can strongly influence the sensitivity of animals to ethanol's behavioral and toxic effects (1, 3-5, 7). Studies in mice indicate that the potency of lethal ethanol doses decreases as body temperature is decreased by ambient temperature challenge during intoxication (3, 4, 7): The most extensive study found that the 8-hour LDso in C57 mice increased from 5.3 g/kg to 8.7 g/kg as body temperatures decreased from 37.9 to 22.6°C (7). In addition, drugs which produce hypothermia pharmacologically have been shown to protect against acute ethanol toxicity (5), providing further support for the hypothesis that a decrease in body temperature may have a protective effect against ethanol lethality. These results in laboratory animals suggest that body temperature manipulation may represent a method of reducing lethality in human ethanol overdoses. In view of recent reports that alcohol-in-combination ranks first on the National Institute of Drug Abuse's list of top problem drugs (2) and represents a large percentage of overdose cases treated in hospital emergency rooms (2,10), it is important to determine if the protective effect of decreased body temperature on ethanol lethality extends to conditions where ethanol is present in combination with other depressant drugs. The purpose of the present study was to begin to address this issue by investigating the effect of body temperature manipulation on lethal doses of ethanol given alone and in combination with pentobarbital.
Drug-naive, male C57BL/6J mice (49--64 days old) were used as subjects. The animals were reared at 21-23°C at Jackson Labs (Bar Harbor, ME) and, upon arrival were acclimated to a 12-hour light:dark cycle (0700 on) in a room maintained at 22---I°C for at least 1 week before experimentation. Between 10:30 and 11:45, an animal's baseline rectal temperature was measured (1) before it was injected intraperitoneally (IP) with 7.8 g/kg ethanol (20% w/v solution in normal saline) or with a combination of 7.8 g/kg ethanol followed by 20 mg/kg pentobarbital (1 mg/ml solution in normal saline). Immediately following injection, the mice were singly housed and exposed to ambient temperatures of 20, 25, 30 or 35°(2 for 24 hours. Mortality was determined at 1, 2, 4, 8 and 24 hours postinjection. Rectal temperatures were measured in the surviving animals immediately following the mortality determination. The number of animals per group was 30 at the start of experimentation and decreased across time due to mortality. Statistical comparisons utilized chi-square analysis (lethality data) and two-tailed t-tests (rectal temperature data). A p value of
0741-8329/91 $3.00 + .00
Body Temperature Influences Ethanol and Ethanol/Pentobarbital Lethality in Mice D E B O R A H A. F I N N , P E T E R J. S Y A P I N , I M A R I N A B E J A N I A N , B R E N D A L. JONES A N D R O N A L D L. A L K A N A 2
Alcohol and Brain Research Laboratory, School of Pharmacy University of Southern California, Los Angeles, CA 90033 Received 30 May 1990; Accepted 15 A u g u s t 1990
FINN, D. A., P. J. SYAPIN, M. 13EJANIAN, B. L. JONES AND R. L. ALKANA. Body temperature influences ethanol and ethanol/pentobarbital lethality in mice. ALCOHOL 8(1) 39-41, 1991.--The effect of body temperature on ethanol (ETOH) or ethanol plus pentobarbital (ETOI-I/PB) lethality was investigated in C57BI./6J mice. Decreasing ambient temperatures from 35-20°C~ decreased rectal temperatures from 38-200C and increased 8-hour survival from 0-93% for ETOH-treated and from 0-100% for ETOH/PB-treated mice. ETOH and ETOH/PB animals with no hypothermia (body temperatures= 38"C) had the highest lethality. Those with body temperatures between 30-32"C had the highest 24-hour survival. These results suggest that conu'olled hypothermia may be useful in reducing lethality from ethanol or ethanol/combination overdoses. Body temperature
Lethality
Ethanol
Pentobarbital
Mice
METHOD
MANIPULATION of body temperature during intoxication can strongly influence the sensitivity of animals to ethanol's behavioral and toxic effects (1, 3-5, 7). Studies in mice indicate that the potency of lethal ethanol doses decreases as body temperature is decreased by ambient temperature challenge during intoxication (3, 4, 7): The most extensive study found that the 8-hour LDso in C57 mice increased from 5.3 g/kg to 8.7 g/kg as body temperatures decreased from 37.9 to 22.6°C (7). In addition, drugs which produce hypothermia pharmacologically have been shown to protect against acute ethanol toxicity (5), providing further support for the hypothesis that a decrease in body temperature may have a protective effect against ethanol lethality. These results in laboratory animals suggest that body temperature manipulation may represent a method of reducing lethality in human ethanol overdoses. In view of recent reports that alcohol-in-combination ranks first on the National Institute of Drug Abuse's list of top problem drugs (2) and represents a large percentage of overdose cases treated in hospital emergency rooms (2,10), it is important to determine if the protective effect of decreased body temperature on ethanol lethality extends to conditions where ethanol is present in combination with other depressant drugs. The purpose of the present study was to begin to address this issue by investigating the effect of body temperature manipulation on lethal doses of ethanol given alone and in combination with pentobarbital.
Drug-naive, male C57BL/6J mice (49--64 days old) were used as subjects. The animals were reared at 21-23°C at Jackson Labs (Bar Harbor, ME) and, upon arrival were acclimated to a 12-hour light:dark cycle (0700 on) in a room maintained at 22---I°C for at least 1 week before experimentation. Between 10:30 and 11:45, an animal's baseline rectal temperature was measured (1) before it was injected intraperitoneally (IP) with 7.8 g/kg ethanol (20% w/v solution in normal saline) or with a combination of 7.8 g/kg ethanol followed by 20 mg/kg pentobarbital (1 mg/ml solution in normal saline). Immediately following injection, the mice were singly housed and exposed to ambient temperatures of 20, 25, 30 or 35°(2 for 24 hours. Mortality was determined at 1, 2, 4, 8 and 24 hours postinjection. Rectal temperatures were measured in the surviving animals immediately following the mortality determination. The number of animals per group was 30 at the start of experimentation and decreased across time due to mortality. Statistical comparisons utilized chi-square analysis (lethality data) and two-tailed t-tests (rectal temperature data). A p value of
