Individual differences in sensitivity to psychoactive drugs are determined by many factors (eg, historical factors including drug history, environmental factors such as social setting and learned associations, and constitutional factors such as genetics). Among these, the notion that genotype may predispose some individuals to extremes of drug sensitivity to a number of compounds has gained much recent support. There is still little information, however, regarding the extent to which genetic predisposition to the effects of one class of drugs also predisposes to another class. Similarly, we have only rudimentary knowledge about the genetic relatedness of sensitivity, tolerance, and physical dependence. The proposed research will establish the genetic basis for sensitivities o several behavioral effects (oral self-administration, acute thermal response, behavioral activation and depression, loss of righting reflex, and rotarod ataxia) of the agents diazepam, morphine, phenobarbital, pentobarbital, and ethanol. Several doses of each compound will be tested in twenty inbred strains of mice. Differences in sensitivity between strains will be taken as evidence for genetic predisposition. Correlation of mean train sensitivities will provide evidence for the generality of genetic predisposition to these compounds. All strains will also be rendered physically dependent upon each compound, and the severity of withdrawal assessed. The genetic correlations between sensitivity and withdrawal among he compounds will thus also be estimated. These results should provide rigorous, systematic evidence for or against e hypothesis that genetic predisposition to a number of psychoactive drugs which share some CNS depressant properties in common generalizes across drugs of different pharmacological classes and may ultimately lead to a better understanding of compulsive drug self-administration.
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