We have developed a new model of cryptogenic infantile spasms with prenatal betamethasone brain priming to increase susceptibility to development-specific spasms triggered byN-methyl-d-aspartate (NMDA). A recent clinical study linked severe prenatal stress to increased risk for development of infantile spasms. Here, we determined whether prenatal restraint stress (2 × 45 min) in rats on gestational day 15 would increase susceptibility to develop spasms on postnatal day 15. Prenatal stress significantly accelerated onset and increased number of NMDA-triggered spasms compared to handled controls. A single adrenocorticotropic hormone (ACTH or corticotropin) dose delivered acutely had no effects, whereas long-term (3 day) ACTH pretreatment significantly increased latency to onset and decreased number of spasms (an effect similar to that in the human condition). Our data support the notion that extra care should be provided during pregnancy to minimize stress.