Neurobehavioral and metabolic long-term consequences of neonatal maternal deprivation stress and adolescent olanzapine treatment in male and female rats.

Early maternal deprivation (MD), 24h of dam-litter separation on postnatal day (PND) 9, has been proposed as a suitable animal model to investigate some neuropsychiatric disorders with a base in neurodevelopment that also compromises metabolic and endocrine homeostasis. Atypical antipsychotics are frequently prescribed to children and adolescents as first-line treatment for several mental disorders despite the adverse metabolic effects frequently reported. However, persistent long-term effects after adolescent drug therapy have been scarcely investigated. In the present study we aimed to investigate the long-lasting metabolic and behavioral effects of MD in combination with the administration of an atypical antipsychotic, i.e. olanzapine, during adolescence. For that purpose, male and female Wistar rats not exposed (control group, Co) and exposed to the MD protocol were administered with oral olanzapine (Olan, 7.5mg/kg/day) or vehicle (Vh, 1mM acetic acid) in drinking water from PND 28 to PND 49. Body weight gain, glycaemia and plasma triglyceride (TG) levels were evaluated as relevant metabolic parameters. MD significantly diminished body weight gain, while Olan administration only induced a subtle decrease in body weight gain among female animals in the long-term. Olan discontinuation decreased plasma TG levels in adult rats, an effect that was counteracted by neonatal exposure to the MD protocol. Both MD and Olan treatment impaired cognitive function in the novel object recognition test, although no interaction between treatments was observed. Neither MD nor Olan administration affected psychotic-related symptoms evaluated in the prepulse inhibition task, although animals treated with Olan showed an increased reactivity to the first acoustic stimulus. MD diminished the corticosterone stress-induced response among females, and reduced the expression of CB1 receptors in the hippocampus of both male and female rats. Notably, Olan administration tended to counterbalance these two MD-induced effects (i.e. corticosterone response and CB1 receptor expression). Present findings provide evidence for the long-lasting effects of neonatal MD and Olan administration during adolescence, and suggest some sex-dependent interactions between these two protocols. Further research on the interactions between early life stress and antipsychotic drugs is urgently needed, and sex differences should be consistently considered both in animal models and in translation to human studies.