Low-dose neonatal domoic acid causes persistent changes in behavioural and molecular indicators of stress response in rats

► We investigated CNS markers of stress-response following neonatal domoic acid exposure. ► Behavioral testing showed increased anxiety, perseveration and altered search strategies. ► Sex differences in both adrenergic and corticosteroid receptor expression were found. ► Early-life exposure to domoate alters indicators of altered stress response. Appropriate stress responses rely on a finely-tuned neuronal balance that must continually adapt to a frequently changing external environment. Alterations in this balance can result in susceptibility to a variety of stress-related disorders, as well as exacerbate already existing conditions. We have previously reported that rat pups injected with a very low dose (20μg/kg) of domoic acid during the second postnatal week of life display low-grade seizure behaviours when challenged with stressful tasks, and also exhibit a variety of structural and functional changes similar to those seen in temporal lobe epilepsy. The current study was designed to investigate markers of altered stress-response in this model. Following neonatal treatment, adult rats were tested in the elevated plus maze, as well as two water maze tasks, both of which involved a platform reversal challenge. Results indicated a modified behavioural stress/anxiety response, increased perseveration, and alterations in search strategy for all domoate-treated rats, as well as male-specific deficits in cognitive flexibility. In addition, 80% of treated males and 20% of treated females exhibited seizure behaviour. Western blot analysis revealed male-only increases in adrenergic receptor (α2a and α2c) and mineralocorticoid receptor expression, and subtle sex-specific changes in glucocorticoid receptor expression, but no differences in corticotropin-releasing factor receptors I/II, or dopamine D2 receptor expression. A significant decrease in glucocorticoid:mineralocorticoid ratio was also noted. We conclude that early exposure to DOM alters central mechanisms underlying stress response, and that this model may be valuable for investigating the connection between stress and neurological disorders.