Adult rats treated with risperidone during development are hyperactive.

Abstract

Risperidone is an antipsychotic drug approved for use in children, but little is known about the long-term effects of early-life risperidone treatment. In animals, prolonged risperidone administration during development increases forebrain dopamine receptor expression immediately upon the cessation of treatment. A series of experiments was performed to ascertain whether early-life risperidone administration altered locomotor activity, a behavior sensitive to dopamine receptor function, in adult rats. One additional behavior modulated by forebrain dopamine function, spatial reversal learning, was also measured during adulthood. In each study, Long-Evans rats received daily subcutaneous injections of vehicle or one of two doses of risperidone (1.0 and 3.0 mg/kg per day) from postnatal days 14 – 42. Weight gain during development was slightly yet significantly reduced in risperidone-treated rats. In the first two experiments, early-life risperidone administration was associated with increased locomotor activity at one week post-administration through approximately nine months of age, independent of changes in weight gain. In a separate experiment, it was found that the enhancing effect of early-life risperidone on locomotor activity occurred in males and female rats. A final experiment indicated that spatial reversal learning was unaffected in adult rats administered risperidone early in life. These results indicate that locomotor activity during adulthood is permanently modified by early-life risperidone treatment. The findings suggest that chronic antipsychotic drug use in pediatric populations (e.g., treatment for the symptoms of autism) could modify brain development and alter neural set-points for specific behaviors during adulthood.

Early-life risperidone enhances locomotor responses to amphetamine during adulthood

“…Testing occurred between noon and 4:00 p.m. each day. These tests determined if rats administered risperidone early in life were more active several days after the end of the risperidone administration on postnatal day 42, as reported previously (Bardgett et al, 2013). …”

“…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).…”

“…For example, daily risperidone administration for four weeks up-regulates dopamine D 2 and D 4 receptors in several forebrain regions in juvenile and adult rats but only elevates dopamine D 1 receptors in the nucleus accumbens and caudate putamen in the younger group (Moran-Gates et al, 2007). At a behavioral level, daily risperidone administration between postnatal days 14–42 leads to hyperactivity that lasts for several months after cessation of treatment (Bardgett et al, 2013). These findings raise concerns that early-life risperidone administration could lead to an enhancement in behavioral sensitivity to drugs that target dopamine synapses during adulthood.…”

Evaluating long-term consequences of adolescent antipsychotic exposure

“…However, a recent study reported that adult rats treated with aripiprazole or risperidone treatment in adolescence spent longer time in the centre and the open part in EPM and these findings were selective to males (De Santis et al 2016). Reversal learning in T maze in adulthood was also not altered by chronic risperidone administration in juvenile and early-adolescent period (Bardgett et al 2013). However, chronic adolescent exposure to typical APDs seems to have adverse outcomes on these measures.…”

“…In another study, rats treated subcutaneously with risperidone, an atypical APD, from PND14 to PND42, which spans both juvenile and early-adolescent periods in rats, were observed to have spontaneous hyperlocomotion at the 7 th day of drug withdrawal (i.e. PND49) (Bardgett et al 2013). This increased motor activity in both males and females was more robust with a higher dose (3 mg/kg) of risperidone, compared with the lower dose (1 mg/kg), and persisted until PND270.…”