Early-life risperidone administration alters maternal–offspring interactions and juvenile play fighting

Abstract

Risperidone is an antipsychotic drug that is approved for use in childhood psychiatric disorders such as autism. One concern regarding the use of this drug in pediatric populations is that it may interfere with social interactions that serve to nurture brain development. This study used rats to assess the impact of risperidone administration on maternal-offspring interactions and juvenile play fighting between cage mates. Mixed-sex litters received daily subcutaneous injections of vehicle or 1.0 or 3.0 mg/kg of risperidone between postnatal days (PNDs) 14-42. Rats were weaned and housed three per cage on PND 21. In observations made between PNDs 14-17, risperidone significantly suppressed several aspects of maternal-offspring interactions at one-hour post-injection. At 23 hours post-injection, pups administered risperidone had lower activity scores and made fewer non-nursing contacts with their moms. In observations of play-fighting behavior made once a week between PNDs 22-42, risperidone profoundly decreased many forms of social interaction at one hour post-injection. At 23 hours post-injection, rats administered risperidone made more non-social contacts with their cage mates, but engaged in less social grooming. Risperidone administration to rats at ages analogous to early childhood through adolescence in humans produces a pattern of abnormal social interactions across the day that could impact how such interactions influence brain development.

Delayed yet persistent effects of daily risperidone on activity in developing rats

“…Admittedly, the doses used here were higher than those typically administered to adult rats in order to characterize the more nuanced effects of risperidone on locomotor activity (Arnt, 1995; Bardgett et al, 2006). However, the selected doses were chosen based on their clinical relevance (Kapur et al, 2003) and their consistency with recent work on the behavioral and biochemical effects of early-life risperidone (Moran-Gates et al, 2007; Choi et al, 2009; 2010; Bardgett et al, 2013; Gannon et al, 2015). The reduced activity observed in developing rats administered risperidone is consistent with the effects of haloperidol or clozapine on activity in rats between the ages of PND 21 and adulthood (Wiley, 2008).…”

“…This latter dose was also considered because it is possible that some children receive risperidone doses that are at or above those recommended for adults. Finally, these doses were the same as those used in our recent behavioral studies of early-life risperidone administration (Bardgett et al, 2013; Gannon et al, 2015) as well as in studies demonstrating significant changes in forebrain receptor binding after early-life administration (Moran-Gates et al, 2007; Choi et al, 2009; 2010). …”

“…As a means of gauging if and when the hyperactivity observed after the cessation of risperidone administration actually emerged during the course of daily treatment, locomotor activity was also recorded at 23 hours post-injection and thereafter once a week at the same post-injection time point, in developing and adult rats. It is unlikely that locomotor activity at this time point is influenced by residual risperidone in plasma since plasma and brain half-lives of risperidone in adult rats are approximately one and 3.5 hours respectively (van Beijsterveldt et al, 1994; Olsen et al, 2008), and our own work has demonstrated that risperidone is undetectable in the plasma of developing rats at 23 hours post-injection (Gannon et al, 2015). Finally, locomotor activity was measured one week after the cessation of daily risperidone administration, in order to determine if such administration led to enduring hyperactivity in younger and older rats.…”

Early-life risperidone enhances locomotor responses to amphetamine during adulthood

“…The doses of risperidone were based on our previous behavioral work (Bardgett et al, 2013; Gannon et al, 2015; Stevens et al, 2016) and reports from others demonstrating the effects of early-life risperidone on neurotransmitter receptor levels (Choi et al, 2009, 2010; Moran-Gates et al, 2007). Beyond these precedents, the 1.0 mg/kg dose was selected because it acutely reduces amphetamine-induced hyperactivity by 50% (a powerful preclinical predictor of antipsychotic drug activity) (Arnt, 1995) and occupies 60–80% of dopamine D 2 receptors in rat forebrain – a degree of receptor blockade associated with antipsychotic drug efficacy in humans (Kapur et al, 2003).…”

The effects of amphetamine on working memory and locomotor activity in adult rats administered risperidone early in life

“…The dose of risperidone used (3.0 mg/kg, sc) was based on our previous behavioral work [13–15,28] and reports demonstrating the effects of early-life risperidone on neurotransmitter receptor levels [18,19,21]. Risperidone was dissolved in a small volume of 10% glacial acetic acid, brought to volume with 0.9% saline, and adjusted to a pH ~6.2 with 1M sodium hydroxide.…”