Abstract: The hypothalamo-pituitary-adrenal (HPA) axis plays a crucial role in stress. One of its central regulatory components is arginine-vasopressin (AVP). We studied the role of AVP in acute restraint in AVP-deficient mutant Brattleboro rats (AVP−), but our results were variable. The early life period is important in the later stress reactivity of the animals. We realized that our AVP− pups could be born from AVP+ (heterozygous) or from AVP− mothers. Therefore, we asked whether the genotype of the mother could explain the variability. Adult rats from AVP+ and AVP− mothers were stressed with 60 min of restraint. Trunk blood was collected for measuring hormone content by radioimmunoassay. All offspring of AVP+ mothers had similar adrenocorticotropic hormone (ACTH) responses to restraint, whereas the AVP− rats born to AVP− mothers showed reduced ACTH reactivity. Our results show that the AVP− genotype of the mother can decrease the stress reactivity of AVP− Brattleboro rats. In mutant/knockout animals, family background should be taken into account as well as the genotype of the studied animals.