Selective breeding of rats differing in sensitivity to the effects of acute ethanol administration.

Selective breeding of rats for sensitivity to the anesthetic effects of ethanol is being carried out with rats derived from the genetically heterogeneous N/Nih stock. Thirteen generations of within family selection have been achieved with replicate high (HAS), low (LAS) and control alcohol sensitive (CAS) lines. Significant separation between lines on sleep time and blood ethanol concentration (BEC) at awakening following ethanol administration has been achieved. In general, the results obtained so far replicate the findings with short (SS) and long (LS) sleep mice. One exception is that the high alcohol sensitivity rats (HAS) also appear more sensitive to pentobarbital relative to LAS rats. This finding is opposite to that which occurs with SS and LS mice where the low ethanol sensitive SS mice appear more sensitive to pentobarbital than the LS mice.

gamma-Aminobutyric acid-activated chloride channels: relationship to genetic differences in ethanol sensitivity.

We demonstrated recently that low concentrations of ethanol enhanced the muscimol-stimulated chloride influx in cerebellar membranes from long sleep (LS-ethanol sensitive) mice, but had no effect on membranes from short sleep (SS-ethanol resistant) mice. The LS and SS were selected from a heterogeneous stock (HS) of mice for differential sensitivity to the hypnotic effects of ethanol as measured by the duration of the loss of the righting reflex (sleep time). In the present study, we tested 100 HS for ethanol sleep time. The mice with the shortest sleep time (HS-SS) and the mice with the longest sleep time (HS-LS) were selected and tested for the effect of ethanol and muscimol on chloride flux in cerebellum. The effects of ethanol and muscimol on both cerebellar and cortical chloride flux were also examined in rats from the 7th generation selected for differential sensitivity to the hypnotic effects of ethanol (high acute ethanol sensitive rats-HAS and low acute ethanol sensitive rats-LAS). Low concentrations of ethanol (10-30 mM) potentiated muscimol stimulation of 36Cl- uptake in both cortical and cerebellar membranes prepared from ethanol-sensitive animals (HS-LS and HAS). None of the ethanol concentrations tested altered stimulated chloride uptake in ethanol-resistant animals (HS-SS and LAS). No differences in muscimol stimulation of chloride uptake were observed between the pairs of selected lines. These findings strongly suggest that genetic differences in ethanol hypnosis are related to differences in the sensitivity of gamma-aminobutyric acid-operated chloride channels to ethanol.

Genetic correlation of ethanol-induced ataxia and cerebellar Purkinje neuron depression among inbred strains and selected lines of rats.

In the present study, we compared phenotypic differences in behavioral and neurophysiological responses to acute ethanol administration among six inbred rat strains. Genetic variation was found both for ataxia, as measured by loss of righting response (sleep time) after a hypnotic dose of ethanol, and for the depressant action of ethanol on the spontaneous discharge of cerebellar Purkinje neurons. Results from an analysis of covariance of these phenotypes, measured among the inbred strains, provided strong evidence for a high genetic correlation between sleep time and inhibition of cerebellar Purkinje neuron discharge in response to acute ethanol administration. However, ethanol metabolism was also found to correlate with the behavioral sensitivity of rats to ethanol. Preliminary data from the third generation of replicate lines of rats currently being selectively bred for high and low acute sensitivity to ethanol shows a trend toward divergence of both ethanol sleep time and neuronal sensitivity to acute ethanol. The conclusion from these data supports the hypothesis that the cerebellum is an important locus of ethanol action, and suggests that neuronal sensitivity to ethanol will continue to diverge between these rat lines as selection for the sleep time phenotype progresses.

Application of a high performance liquid chromatography method for screening of aldehyde dehydrogenase isozyme deficiency in hair roots from different ethnic groups.

A sensitive high performance liquid chromatography method has been used to measure aldehyde dehydrogenase (ALDH) activity in hair roots from Caucasian and Japanese subjects. Kinetic studies confirmed previous isoelectric focusing results that hair roots from Caucasians have two forms of ALDH, one low Km form and another high Km form, while hair roots from Japanese individuals who show a flushing reaction after ethanol intake lack, or have low activity of, the low Km form. By taking the ratio of the activities measured at a low (3 microM) and a high (75 microM) concentration of the substrate (3,4-dihydroxyphenylacetaldehyde), a suitable index for ALDH deficiency was obtained. The ratio varied between 1.6 and 3.5 for Caucasians and between 7 and 23 for Japanese flushers, and it was 2.5 for a Japanese nonflusher. The current method allows a more quantitative and qualitative assessment of the ALDH isozyme pattern in hair roots than that obtained with the isoelectric focusing technique.

Effects of phencyclidine, amphetamine and related compounds on dopamine release from and uptake into striatal synaptosomes.

The ability of phencyclidine (PCP), amphetamine and other substances to stimulate dopamine release from and inhibit dopamine uptake into rat striatal synaptosomes was examined in a continuous superfusion system. Inhibition of uptake was measured by determining inhibition of [3H]dopamine displacement by unlabeled dopamine ([1H]dopamine). The displacement of [3H]dopamine by 10(-7) M [1H]dopamine was temperature- and sodium-sensitive and calcium-independent. [1H]Dopamine was an order of magnitude more potent than serotonin or norepinephrine in displacing [3H]dopamine. The concentrations of reserpine required to inhibit [3H]dopamine uptake and [3H]dopamine displacement by [1H]dopamine were similar. Nomifensine, benztropine, PCP and amphetamine also inhibited the displacement of [3H]dopamine by [1H]dopamine at concentrations which have been shown previously to inhibit the uptake of [3H]dopamine, suggesting that the mechanism behind displacement and uptake are very similar. PCP, at 10(-7) to 10(-5) M, significantly inhibited [3H]dopamine displacement by 10(-7) M [1H]dopamine, PCP was less potent than nomifensine or benztropine in inhibiting [3H]-dopamine displacement by 10(-7) M [1H]dopamine, but was equipotent to amphetamine. Superfusion of the synaptosomes for 6 min with PCP, 10(-6)M, induced increases in the spontaneous release of dopamine. In this regard, PCP was less potent than amphetamine, reserpine, flupenthixol, or benztropine. Upon initial exposure of the synaptosomes to amphetamine at 10(-7) to 10(-5) M, a substantial calcium-dependent release of dopamine was induced. In contrast, PCP did not stimulate the early calcium-dependent release of dopamine. These results indicate that PCP is less potent than amphetamine at releasing dopamine and may affect dopamine metabolism in the striatum primarily by inhibiting the reuptake of this catecholamine.

Comparison of parent-offspring resemblance for specific cognitive abilities.

A battery of cognitive ability tests identical to that used in the Hawaii Family Study was administered to a set of Caucasian families who participated in the Boulder Family Study. Resemblances between parents and offspring were compared with those from the Hawaii, Korean, and other recent family studies, using the same cognitive tests. Estimates from these studies indicate that values for parent-offspring resemblance are nonzero and fall around the midrange of possible values.

Response to Selection for Mating Speed and Changes in Gene Arrangement Frequencies in Descendants from a Single Population of DROSOPHILA PSEUDOOBSCURA.

Heritability estimates, based on 19 generations of selection for fast and slow mating speed, were not significantly different from zero at the 0.05 level in any replicate of selected lines in a population of flies descended from the Mather population in California. Only the combined heritability estimate of approximately 2% was significant. This indicated that very little additive genetic variance was present in the base population and that strong directional selection for rapid mating may have occurred in the previous history of the local population at Mather and/or during its many generations of laboratory propagation. Frequencies of third chromosome gene arrangements were monitored during the course of selection. Balancing selection, unrelated to that imposed for mating speed, and genetic drift appeared to be the major factors causing changes in chromosome frequencies. Present differences in adaptive value of third chromosome variants in nature may be associated with nonadditive effects on mating speed, as well as effects on other components of fitness.

Assortative marriage for cognitive abilities.

One hundred and twenty-three spouse pairs gathered as part of a family study of the genetics of special abilities were examined on a battery of ability tests. Four principal components were interpreted after rotation: Spatial, Verbal, Perceptual Speed, and Memory. In addition, the first factor from a common factor analysis (unrotated) was taken as an estimate of g. Assortive marriage was measured by the spouse correlations on the test and factor scores. Three multiple regression models were designed to determine whether phenotypic convergence during marriage occurs and whether resemblance between spouses in cognitive ability is related to fertility. The following independent variables were partialed out in the models: (1) sex and age; (2) sex, age, and length of marriage; and (3) sex, age, and number of children. Model 1 (age and sex) accounted for part of the correlation between spouses on the spatial tests, the verbal tests and the spatial and general factors. The perceptual speed and memory tests and factors were largely unaffected by partialing out the independent variables. No evidence of phenotypic convergence over years of marriage or of a relationship between fertility and resemblance in abilities was found.