Quantitative Trait Locus (QTL) mapping has suggested that the gene coding for the serotonin 5-HT1B receptor subtype may influence several responses to ethanol. Preliminary data suggest that 5-HT1B knockout mice that lack this gene show excessive alcohol drinking, reduced sensitivity to ethanol-induced ataxia, possibly attenuated tolerance, but comparable acute ethanol withdrawal, relative to their wild-type counterparts. Mouse 5-HT1B receptors have been localized predominantly in axon terminals of the globus pallidus, substantia nigra, dorsal subiculum, raphe, and cerebellar deep nuclei. However, the specific neural 5-HT1B receptor population(s) that may be affecting these ethanol responses is unknown. We propose in Aims 1-3 to use congenic chimeras between 5-HT1B knockout and wild-type mice, to identify specific 5-HT1B receptor populations that subserve individual alcohol drinking and ataxia scores.
In Aim 4, the 5-HT1B receptor will be reexpressed in specific parts of the brains of 5-HT1B knockout mice to test the hypothesis that the 5-HT1B heteroreceptors, rather than the autoreceptors, are responsible for the altered phenotype(s) of the knockout mice. It is expected that alcohol preference and ataxia will be altered by reinstatement of particular receptor populations. These studies will allow us to target specific aspects of neuropharmacology in functional studies to be performed later.
In Aim 5, inducible knockouts will be produced, in which mice develop with normal levels of 5-HT1B gene expression that can be inhibited in adulthood. This will permit examination of the role that possible compensatory changes during development might play in determining alcohol drinking and ataxia. Finally, Aim 6 will continue the characterization of 5-HT1B and wild-type mice for additional motor and other behavioral responses to ethanol. These studies will serve as a preamble to future investigations using the approaches outlined above, with the intention of performing neurogenetic analyses with chimeras, tissue-specific and inducible knockouts for those phenotypes which prove to be associated with the 5-HT1B receptor.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Special Emphasis Panel (ZRG4-ALTX-1 (02))
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Oregon Health and Science University
Other Basic Sciences
Schools of Medicine
United States
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Browman, K E; Rustay, N R; Nikolaidis, N et al. (2000) Sensitivity and tolerance to ethanol in mouse lines selected for ethanol-induced hypothermia. Pharmacol Biochem Behav 67:821-9
Morikawa, H; Manzoni, O J; Crabbe, J C et al. (2000) Regulation of central synaptic transmission by 5-HT(1B) auto- and heteroreceptors. Mol Pharmacol 58:1271-8
Boehm 2nd, S L; Schafer, G L; Phillips, T J et al. (2000) Sensitivity to ethanol-induced motor incoordination in 5-HT(1B) receptor null mutant mice is task-dependent: implications for behavioral assessment of genetically altered mice. Behav Neurosci 114:401-9
Boehm 2nd, S L; Crabbe, J C; Phillips, T J (2000) Sensitivity to ethanol-induced motor incoordination in FAST and SLOW selectively bred mice. Pharmacol Biochem Behav 66:241-7
Crabbe, J C; Phillips, T J; Buck, K J et al. (1999) Identifying genes for alcohol and drug sensitivity: recent progress and future directions. Trends Neurosci 22:173-9
Crabbe, J C; Phillips, T J (1998) Genetics of alcohol and other abused drugs. Drug Alcohol Depend 51:61-71