Stress plays a role in the development and severity of psychotic symptoms and there may be a genetic component to stress vulnerability in schizophrenia. Using an established mouse model for schizophrenia, we investigated the behavioural and endocrine response of Nrg1 transmembrane domain mutant mice (Nrg1 HET) and wild type-like (WT) littermates to acute restraint stress. Animals were screened at 3-4 months and 6-7 months of age (before and after onset of hyperlocomotion) for open field behaviour and serum corticosterone levels. In younger mice, stress reduced locomotive and explorative measures and increased anxiety-like behaviour regardless of genotype. Older Nrg1 mutants were less susceptible to the effects of stress on anxiety-related behaviours. All mice responded to restraint stress with robust increases in serum corticosterone. Importantly, the stress-induced increase in corticosterone was more pronounced in Nrg1 mutant than WT mice at the younger but not the older age. Our results suggest that transmembrane domain Nrg1 has only a moderate effect on the acute stress response of mice. The behavioural differences detected between WT and Nrg1 HET mice at the older age were evident without parallel modifications to the glucocorticoid system.