Ethanol tolerance and withdrawal severity in high drinking in the dark selectively bred mice.
BACKGROUND
Mouse lines are being selectively bred in replicate for high blood ethanol concentrations (BECs) achieved after limited access of ethanol (EtOH) drinking early in the circadian dark phase. High Drinking in the Dark-1 (HDID-1) mice are in selected generation S21, and the replicate HDID-2 line in generation S14. Tolerance and withdrawal symptoms are 2 of the 7 diagnostic criteria for alcohol dependence. Withdrawal severity has been found in mouse studies to be negatively genetically correlated with EtOH preference drinking.


METHODS
To determine other traits genetically correlated with high DID, we compared naïve animals from both lines with the unselected, segregating progenitor stock, HS/Npt. Differences between HDID-1 and HS would imply commonality of genetic influences on DID and these traits.


RESULTS
Female HDID-1 and HDID-2 mice tended to develop less tolerance than HS to EtOH hypothermia after their third daily injection. A trend toward greater tolerance was seen in the HDID males. HDID-1, HDID-2, and control HS lines did not differ in the severity of acute or chronic withdrawal from EtOH as indexed by the handling-induced convulsion (HIC). Both HDID-1 and HDID-2 mice tended to have greater HIC scores than HS regardless of drug treatment.


CONCLUSIONS
These results show that tolerance to EtOH's hypothermic effects may share some common genetic control with reaching high BECs after DID, a finding consistent with other data regarding genetic contributions to EtOH responses. Withdrawal severity was not negatively genetically correlated with DID, unlike its correlation with preference drinking, underscoring the genetic differences between preference drinking and DID. HDID lines showed greater basal HIC scores than HS, suggestive of greater central nervous system excitability.
Portland Alcohol Research Center, Department of Behavioral Neuroscience, Oregon Health, Portland, OR 97239, USA. crabbe@ohsu.edu
John C
JC
Crabbe
Alexandre M
AM
Colville
Lauren C
LC
Kruse
Andy J
AJ
Cameron
Stephanie E
SE
Spence
Jason P
JP
Schlumbohm
Lawrence C
LC
Huang
Pamela
P
Metten
D000428:Alcohol Drinking / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001947:Breeding; D002940:Circadian Rhythm / Q000187:drug effects / Q000235:genetics; D004361:Drug Tolerance / Q000235:genetics; D000431:Ethanol / Q000008:administration & dosage* / Q000009:adverse effects*; D005260:Female; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D012720:Severity of Illness Index; D013045:Species Specificity; D013375:Substance Withdrawal Syndrome / Q000235:genetics* / Q000473:pathology
D000431:Ethanol