Tolerance is a process by which repeated doses of a drug leads to progressively less effect. This process has been implicated in the development of dependence on many drugs of abuse, including alcohol. When animals are tested on measures of motor coordination, rapid tolerance, that which develops during the first 24 hours after an initial dose of ethanol, has been shown to be blocked by NMDA receptor antagonists, and facilitated by NMDA agonists. The current proposal entails the use of a powerful genetic tool, selective breeding, to produce two replicate lines of mice which differ markedly in the degree to which they develop rapid tolerance. The process of selection is thought to cause a divergence between the two lines in the biological systems responsible for the trait. Once the selected lines are developed, they will be examined for differences in NMDA receptor density in the brain, and for sensitivity to NMDA modulators. These analyses will be aimed at identifying the differences in the neuroanatomy and neurochemistry produced by selective breeding. Because tolerance development is an important component of alcohol dependence, elucidating the mechanisms behind tolerance development will eventually lead to a better understanding of the disorder in humans.
| Rustay, Nathan R; Crabbe, John C (2004) Genetic analysis of rapid tolerance to ethanol's incoordinating effects in mice: inbred strains and artificial selection. Behav Genet 34:441-51 |
| Rustay, Nathan R; Wahlsten, Douglas; Crabbe, John C (2003) Influence of task parameters on rotarod performance and sensitivity to ethanol in mice. Behav Brain Res 141:237-49 |
| Rustay, Nathan R; Wahlsten, Douglas; Crabbe, John C (2003) Assessment of genetic susceptibility to ethanol intoxication in mice. Proc Natl Acad Sci U S A 100:2917-22 |
