Response to selection for ethanol-induced locomotor activation: genetic analyses and selection response characterization.

Selectively bred FAST mice are highly susceptible, while SLOW mice are less susceptible, to the locomotor stimulant effects of ethanol. Heritability estimates indicate that approximately 15% of the variance in the FAST lines is of additive genetic origin, while low susceptibility is ostensibly nonheritable. Inbreeding has increased at the rate of 2% per generation, but fertility has been unaffected. Measurement reliability for sensitivity to this ethanol effect was high when measured in both circular (r = 0.6) and square (r = 0.7) open-fields. In addition, our results indicate that we have selected for differences in sensitivity to ethanol rather than for differences in habituation to the test environment. The difference in response to ethanol between FAST and SLOW mice extended to tests varying in duration, and to a range of ethanol doses. We conclude that the divergence between FAST and SLOW mice generalizes to related test parameters, and speculate that the genetic architecture underlying the locomotor stimulant response may be simpler than previously proposed.

Genetic components of ethanol responses.

A powerful technique for determining the role of a particular neurotransmitter in mediating a response to ethanol (EtOH) is the analysis of selectively bred lines of animals. Lines selected for sensitivity and resistance to an EtOH effect differ principally in gene frequencies for genes affecting the selected response. Hence, other differences between the lines are likely due to pleiotropic actions of those genes. We discuss behavioral pharmacological experiments in two sets of selected lines. Withdrawal Seizure-Prone (WSP) and -Resistant (WSR) mouse lines were selected for severe and minimal handling-induced convulsions (HIC), respectively, after withdrawal from chronic EtOH inhalation. The HIC is also elevated after acute administration of low doses of convulsant drugs. WSP mice were found to be more sensitive than WSR mice to many such drugs. There was no apparent specificity of such effects to any particular neurotransmitter system. Thus, genetic determination of a behavioral response to EtOH in this case cannot be traced to the influence of a single neurotransmitter system. COLD and HOT mice were selectively bred to show severe and mild hypothermia, respectively, after acute EtOH administration. COLD mice are also more sensitive to a number of other alcohols, barbiturates, and other general central nervous system depressants. When tested for sensitivity to a number of drugs with specific effects on neurotransmitter systems, COLD and HOT mice did not differ in sensitivity to drugs affecting dopaminergic, alpha-adrenergic, or nicotinic acetylcholinergic systems. COLD mice were more sensitive, however, to opioid and serotonergic drugs. Thus, analysis of these selected lines was successful in identifying particular neurotransmitters which may be important in EtOH-induced hypothermia.

Indexing withdrawal in mice: matching genotypes for exposure in studies using ethanol vapor inhalation.

Withdrawal Seizure-Prone (WSP) and -Resistant (WSR) mice have been bidirectionally selected for severity of handling-induced convulsions (HIC) following withdrawal from 72 hr of chronic ethanol vapor inhalation. During selection, daily injections of the alcohol dehydrogenase inhibitor, pyrazole, were used to enhance and stabilize blood ethanol concentrations (BEC). After 26 generations of selection, WSR mice show lower withdrawal BEC than WSP mice exposed to the same ethanol vapor concentrations. Because it is desirable to compare mice maintained at the same BEC to assess correlated responses to selection, this has necessitated exposing WSR mice to higher ethanol vapor concentrations than WSP mice to achieve matched chronic BEC. The experiments reported herein demonstrate two methods for producing matched withdrawal BEC: (1) by exposing mice to the same ethanol vapor concentration and varying the pyrazole dose; and (2) by administering only ethanol at different vapor concentrations and selecting some mice with approximately the same BEC. When exposed to the same ethanol vapor concentration, WSR mice given 1.0 mmol/kg pyrazole had withdrawal BEC equivalent to WSP mice given 0.75 mmol/kg pyrazole. However, WSP mice had much more severe withdrawal HIC than WSR mice. WSP and WSR mice metabolized ethanol at the same rate following withdrawal. The basis for the differential effectiveness of pyrazole is unknown. We also exposed mice to higher ethanol vapor concentrations in the absence of pyrazole. By exposing WSR mice to higher concentrations than WSP, roughly equivalent BEC on withdrawal was achieved. Because BEC are more variable in the absence of pyrazole, it was necessary to select animals of each genotype to achieve relatively matched BEC.(ABSTRACT TRUNCATED AT 250 WORDS)

Response to selection for sensitivity to ethanol hypothermia: genetic analyses.

Selective breeding has been used to produce lines of mice differing in sensitivity to the hypothermic effects of ethanol (EtOH). Two genetically independent HOT (insensitive) and two COLD (sensitive) lines are maintained along with two nonselected control (CON) lines. The breeding program is currently in selected generation 14, and HOT and COLD mice differ by about 4 degrees C in selected hypothermic response. Estimates of heritability indicate that approximately 20% of the variance in EtOH-induced hypothermic response in mice is of additive genetic origin. Inbreeding has increased at a rate of about 1.7% per generation and no fertility problems have been detected as a result of selection. Projects designed to evaluate apparent correlated responses to selection are discussed.