Abstract
Environmental factors such as stress drive the development of drug addiction in genetically vulnerable individuals; the genes underlying this vulnerability are unknown. One strategy for uncovering these genes is to study the impact of environmental manipulation on high-throughput phenotypes that predict drug use and addiction-like behaviors. In the present study, we assessed the viability of this approach by evaluating the relative effects of environmental enrichment and isolation housing on three high-throughput phenotypes known to predict variation on distinct aspects of intravenous drug self-administration. Prior to behavioral testing, male and female C57BL/6J and DBA/2J mice (BXD founders) were housed in enrichment or isolation for ten weeks beginning at weaning. Enrichment significantly reduced novelty reactivity; this effect was significantly more robust in C57BL/6J mice relative to DBA/2J mice. Enrichment significantly reduced novelty preference; this effect was significantly dependent on novel environment characteristics and was significantly more robust in DBA/2J mice relative to C57BL/6J mice. Enrichment significantly increased anxiety; this effect was not strain-dependent. Collectively, these data indicate that (1) environmental enrichment influences novelty reactivity, novelty preference, and anxiety via distinct genetic mechanisms in mice, and (2) the BXD panel can be used to discover the genetic and epigenetic mechanisms underlying this phenomenon.