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/

Previous work has identified inherent behavioral, neuroendocrine, and biochemical differences among inbred rodent strains that have been rel ated 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 diff er between a pair of inbred rat strains (Lewis and Fischer 344) or a p air of inbred mouse strains (A/J and C57BL/6J); (2) which of these tra its might be amenable to quantitative trait locus analysis; and (3) wh ether additional behavioral or biochemical differences relevant to dru g- or stress-responsiveness could be identified in these strains. Spec ifically, we measured several behavioral, neuroendocrine, and biochemi cal traits in parental Lewis and Fischer 344 rats and in 298 members o f an F-2 intercross population, as well as in parental A/J and C57BL/6 J mice and in 11 of the AXB/BXA recombinant inbred mouse strains. Trai ts measured included exploratory locomotor activity in a novel environ ment; 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 D elta FosB, and the protein phosphatase inhibitor DARPP-32; and late-af ternoon plasma corticosterone concentrations. Each of the traits measu red in Fz rats or recombinant inbred mice appears to be influenced by multiple genes, as well as by environmental factors. There were statis tically significant, albeit relatively weak, correlations among severa l traits in an F-2 intercross population bred from Lewis and Fischer r ats. Among the traits studied in Lewis and Fischer rats, one seemed mo st amenable to quantitative trait locus analysis: the level of the inh ibitory G-protein subunit, G alpha(i), in the nucleus accumbens. We al so found a robust genetic correlation between levels of Delta FosB and levels of the dopamine transporter in striatal regions in AXB/BXA rec ombinant inbred mouse strains. While these studies demonstrate the Lik ely complexity of the genetic factors that influence the numerous phen otypes associated with altered responsiveness to drugs of abuse and st ress, they represent an initial and necessary step toward identifying specific genetic factors involved. (C) 1998 Elsevier Science B.V. All rights reserved.