title: Genetic analysis of behavioral, neuroendocrine, and biochemical parameters in inbred rodents: initial studies in Lewis and Fischer 344 rats and in A/J and C57BL/6J mice.
abstract: Previous work has identified inherent behavioral, neuroendocrine, and biochemical differences among inbred rodent strains that have been related to the animals' differential responsiveness to drugs of abuse or stress. In the present study, we sought to determine (1) whether there are genetic correlations among particular phenotypic traits that differ between a pair of inbred rat strains (Lewis and Fischer 344) or a pair of inbred mouse strains (A/J and C57BL/6J); (2) which of these traits might be amenable to quantitative trait locus analysis; and (3) whether additional behavioral or biochemical differences relevant to drug- or stress-responsiveness could be identified in these strains. Specifically, we measured several behavioral, neuroendocrine, and biochemical traits in parental Lewis and Fischer 344 rats and in 298 members of an F2 intercross population, as well as in parental A/J and C57BL/6J mice and in 11 of the AXB/BXA recombinant inbred mouse strains. Traits measured included exploratory locomotor activity in a novel environment; amphetamine-induced locomotor activity; several specific protein levels in striatal regions, including inhibitory G protein subunits, the dopamine transporter, the Fos family member transcription factor DeltaFosB, and the protein phosphatase inhibitor DARPP-32; and late-afternoon plasma corticosterone concentrations. Each of the traits measured in F2 rats or recombinant inbred mice appears to be influenced by multiple genes, as well as by environmental factors. There were statistically significant, albeit relatively weak, correlations among several traits in an F2 intercross population bred from Lewis and Fischer rats. Among the traits studied in Lewis and Fischer rats, one seemed most amenable to quantitative trait locus analysis: the level of the inhibitory G-protein subunit, Galphai, in the nucleus accumbens. We also found a robust genetic correlation between levels of DeltaFosB and levels of the dopamine transporter in striatal regions in AXB/BXA recombinant inbred mouse strains. While these studies demonstrate the likely complexity of the genetic factors that influence the numerous phenotypes associated with altered responsiveness to drugs of abuse and stress, they represent an initial and necessary step toward identifying specific genetic factors involved.
authors.affiliation: Laboratory of Molecular Psychiatry and Center for Genes and Behavior, Yale University School of Medicine, New Haven, CT 06508, USA.
authors.forename: E S
authors.initials: ES
authors.lastname: Brodkin
authors.forename: W A
authors.initials: WA
authors.lastname: Carlezon
authors.forename: C N
authors.initials: CN
authors.lastname: Haile
authors.forename: T A
authors.initials: TA
authors.lastname: Kosten
authors.forename: G R
authors.initials: GR
authors.lastname: Heninger
authors.forename: E J
authors.initials: EJ
authors.lastname: Nestler
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D003342:Corpus Striatum / Q000378:metabolism; D005106:Exploratory Behavior / Q000502:physiology; D019204:GTP-Binding Proteins / Q000378:metabolism; D051379:Mice; D008805:Mice, Inbred A / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL / Q000235:genetics / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009490:Neurosecretory Systems / Q000502:physiology*; D019655:Quantitative Trait, Heritable; D051381:Rats; D011916:Rats, Inbred F344 / Q000235:genetics / Q000378:metabolism; D011917:Rats, Inbred Lew / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic
chemical_list: D000661:Amphetamine; D019204:GTP-Binding Proteins