Trends in Neurosciences
ReviewIdentifying genes for alcohol and drug sensitivity: recent progress and future directions
Section snippets
Mapping methods
Many inbred strains of mice are available for genetic mapping experiments. Within an inbred strain, same-sex animals are essentially monozygotic twins and, furthermore, have two identical copies of a single allele at each locus. When strains are crossed, the F1 generation is heterozygous at all genes that differ in the parents. Crossing F1 mice to obtain an F2, or backcrossing an F1 to one of the parental inbreds, produces a generation that segregates genetically. Initial identification of QTLs
Acute alcohol- and pentobarbitol-withdrawal convulsions
D2-strain mice are known to express severe alcohol-withdrawal convulsions, whereas B6-strain mice have a much milder withdrawal reaction23, 24. Using three populations derived from B6 and D2 (BXD RI strains, an F2 cross and selected lines), Buck et al.11 mapped three QTLs that are associated with increased risk for acute alcohol-withdrawal convulsions (Alcw1–3, see Table 1). Together, these three QTLs account for 68% of the genetic variability in acute alcohol-withdrawal severity among B6- and
Alcohol drinking
McClearn and Rodgers first characterized B6 mice as extreme alcohol ‘preferrers’ and D2 mice as extreme alcohol ‘avoiders’28. In 1994 and 1995, two groups reported provisional mapping of several QTLs for alcohol preference drinking in BXD RI mice14, 29. Four have been confirmed, on chromosomes 1, 2, 4 and 9 (14, 15, 16, 17, 18), and a QTL for the related trait, alcohol acceptance, has been mapped to chromosome 15 (Ref. 19). Marker-based selection was used to verify the acceptance QTL (Ref. 19).
Other drug response QTLs
Standard methods were used to map 5 QTLs (Lore1–5; 21, 32) in mice selected for long (LS) or short (SS) ethanol-induced loss of the righting reflex. Marker-based selection was then used for further verification of these QTLs (Ref. 33). QTLs have also been mapped for cocaine-induced seizures (H.L. Hain, J.C. Crabbe, C.M. Merrill, S.E. Bergeson and J.K. Belknap, unpublished observations). Location of these QTLs is indicated in Fig. 1.
Significant QTLs for morphine preference drinking have been
Methodological advances to increase QTL map resolution
When a QTL is first mapped, the resolution of its location is typically coarse, that is, within 10–30 cM (see Table 1). Darvasi has recently described several options for attaining 1 cM map resolution in the mouse37. These approaches include the use of advanced intercross lines, interval-specific congenic strains and recombinant inbred-segregation tests. While detailed discussion of these methods is beyond the scope of this review, the attainment of finer map resolution is important because it
Knockout approaches
The recent development of gene-targeted mutant mice that lack, underexpress or overexpress specific genes offers an excellent opportunity to evaluate the roles of their gene products in a variety of behaviors. For example, Saudou et al. produced a mouse that completely lacked 5-HT1B receptors40. Because Htr1b was a candidate near a QTL affecting alcohol preference drinking, we tested the 5-HT1B knockout and wild-type controls for alcohol preference. The knockout mice consumed about twice as
Future directions – more complex solutions for complex traits
QTLs detected through mapping approaches could be based on allelic differences that ultimately lead to different gene products for functional genes, that is, those with direct biological function. In such cases, pursuit of candidate functional genes will be beneficial. Alternatively, the QTL could reflect regulatory sequences or the activity of a modifier gene, which itself affects expression of other functional genes. In this case, identification of unknown genes on the basis of their
Pharmacogenetics – past and future
Rapid progress has been made in the past few years towards identifying specific genes that lead to risk of abuse or protection from the abuse of drugs. Drug responses remain a good paradigm for mapping genes for complex behavioral traits, for at least two reasons. First, there is generally a great deal of heritable genetic variance that underlies individual differences in sensitivity to drugs. It is likely that such genetic variability exists because natural selection has not opposed it, for
Acknowledgements
The authors thank Dr Steve Mitchell for Fig. 1 and Dr Kaitlin Browman for her helpful comments on a draft of this manuscript. The authors' research is supported by three grants from the US Department of Veterans Affairs, and by USPHS Grants AA11322, AA11114, AA10760, AA07468, AA06243, DA10913, DA07262 and DA05228.
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