Low-dose antipsychotics ameliorate maternal separation-induced ultrasound vocalization deficits in the...

Beyond its classical function in salt-water homeostasis, vasopressin plays an important role in higher-order brain functions, including social behaviour. Deficits in social communication are core feature of many neurological and psychiatric disorders, including autism spectrum disorder (ASD), and can be modelled in rodents through maternal separation-induced ultrasonic vocalizations (MS-USV, 30-50 kHz). Consistent with its role in social interaction, vasopressin-deficient Brattleboro rat pups emit fewer MS-USVs. We hypothesized that antipsychotics, approved for irritability and related behavioural manifestations in ASD, could normalize this deficit. We studied 7- to 8-day-old vasopressin-deficient Brattleboro pups and compared them with their heterozygous littermates. Each pup was placed in a 2 L glass beaker for 10 min while MS-USV was recorded using a bat detector. We administered haloperidol, clozapine, olanzapine, risperidone, aripiprazole or vehicle and the genotype was determined retrospectively. Vasopressin-deficient pups vocalized significantly less than their counterparts. Low, non-sedative doses of various antipsychotics (except haloperidol) increased MS-USV in vasopressin-deficient pups to levels comparable to controls. However, higher doses, which induced sedation (measured by increased righting reflex latency or negative geotaxis latency) or stress (indicated by elevated adrenocorticotropin and corticosterone levels), reduced MS-USV in control pups as well. These findings indicate that reduced MS-USV in vasopressin-deficient Brattleboro pups provides a useful model for studying impairments in early-life social communication, which may also be highly relevant in the context of ASD. The responsiveness to low-dose pharmacological intervention further supports the model's relevance for investigating mechanisms and potential therapeutic strategies targeting social behavioural alterations.