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 1 of 2 doses of risperidone (1.0 and 3.0 mg/kg per day) from postnatal Days 14 to 42. Weight gain during development was slightly yet significantly reduced in risperidone-treated rats. In the first 2 experiments, early-life risperidone administration was associated with increased locomotor activity at 1 week postadministration through approximately 9 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.

Figure 1

Comparison of body weight across development during early-life risperidone administration from postnatal day 14 – 42. A. and B. represent respective data from the first two experiments with male rats, and C. represents body weight data from the third experiment involving male and females rats. Symbols indicate where the males treated with 3.0 mg/kg of risperidone differed from the vehicle-treated males (*), the males treated with 1.0 mg/kg of risperidone differed from vehicle-treated males (**), the females treated with 3.0 mg/kg of risperidone differed from the vehicle-treated females (§), or both groups of risperidone-treated females differed from vehicle-treated females (§§). All group differences were significant at p < .05 using a Tukey/Kramer post-hoc test.

Figure 2

Male rats treated with risperidone from postnatal days 14 – 42 are more active than vehicle-treated male rats when tested for five days beginning on postnatal day 49. Rats administered the 3.0 mg/kg dose of risperidone were more active on all test days, except for day 2, when compared to the vehicle-treated controls, as indicated by the *. Rats administered 3.0 mg of risperidone early in life were significantly more active on test days 3 and 4 than rats administered 1.0 mg/kg of risperidone early in life, as indicated by the §. All group differences were significant at p < .05 using a Tukey/Kramer post-hoc test.

Figure 3

Adult male rats demonstrate persistently greater locomotor activity when administered risperidone from postnatal days 14 – 42. The asterisks indicate ages when the rats previously administered the 1.0 mg/kg or 3.0 mg/kg dose of risperidone were more active than the rats previously treated with vehicle. All statistically significant differences were at p < .05 using a Tukey/Kramer post-hoc test.

Figure 4

Male and female rats treated with risperidone from postnatal day 14 – 42 are more active for two consecutive test days one week after the cessation of treatment. Asterisks indicate days when rats administered 3.0 mg/kg of risperidone were more active than same-sex, vehicle-treated control rats. Female rats treated with 3.0 mg/kg of risperidone were significantly more active than female rats treated with 1.0 mg/kg of risperidone on day 2 of testing, as indicated by the §. All statistically significant differences were at p < .05 using a Tukey/Kramer post-hoc test.

Figure 5

Acquisition and reversal of a T-maze spatial discrimination task in adult rats administered risperidone on postnatal days 14 – 42. Acquisition testing began on postnatal day 70. There were no significant effects of early-life risperidone administration on correct arm choice during acquisition or reversal testing.