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

Abstract

Antipsychotic drugs are used to manage symptoms of pediatric psychiatric disorders despite the relative absence of research regarding the long-term effects of these drugs on brain development. Using rats as a model, research has demonstrated that administration of the antipsychotic drug, risperidone, during early postnatal development elevates locomotor activity and sensitivity to the locomotor effects of amphetamine during adulthood. Because risperidone targets neurotransmitter receptors and forebrain regions associated with working memory, the present study determined whether early-life risperidone altered working memory during adulthood and its sensitivity to amphetamine-induced impairment. Female and male rats received subcutaneous (sc) injections of risperidone daily on postnatal days 14-42. Early-life risperidone increased spontaneous locomotor activity and amphetamine-induced hyperactivity during adulthood, although the effects were significantly greater in females. Working memory was tested in an operant-based, delayed non-matching-to-sample task. Early-life risperidone did not affect the percentage of correct choices observed during sessions with 0-8 second delays but impaired performance during sessions with 0-24 second delays. In a subsequent set of tests using 0-24 second delays, amphetamine (0.75 and 1.25 mg/kg, sc) significantly reduced the percentage of correct choices at most delays, but risperidone did not exacerbate this effect. These data suggest that early-life risperidone leads to modest deficits in working memory during adulthood, but does not alter the perturbation of working memory by amphetamine.

Keywords: Antipsychotic; Catecholamine; Delayed non-matching-to-sample; Development; Dopamine; Forebrain; Frontal cortex; Learning.

Figure 1.

Locomotor activity summed over 1 hour and averaged across postnatal days 54 – 57. Females were more active than males (p < .0001). * p = .001 vs. vehicle rats collapsed across sex. Each bar represents group mean ± S.E.M.. n = 9 females and 11 males in each Vehicle or Risp 3.0 group.

Figure 2.

Total locomotor activity summed over three hours after injection of saline or 1.0 mg/kg of amphetamine.^a p = .003 vs vehicle females and males administered amphetamine,^b p ≤ .006 - .0001 vs male rats administered vehicle or risperidone respectively, and^c p < .0001 vs vehicle female rats administered saline or amphetamine. Each bar represents group mean ± S.E.M.. n = 9 females and 11 males in each Vehicle or Risp 3.0 group.

Figure 3.

Correct choices averaged across the 0–8 and 0–24 second delay sessions in the delayed non-matching-to-sample task (excluding the first two days of data for each delay session). Female rats made more correct choices during each set of delay sessions (p = .04 & .03 for the 0–8 and 0–24 second sessions respectively). * p = .04 vs. vehicle rats collapsed across sex at the 0 second delay. Each marker represents group mean ± S.E.M.. n = 9 females and 11 males in each Vehicle or Risp 3.0 group.

Figure 4.

Effects of amphetamine on correct choices in the 0–24 second delay version of the non-matching-to-sample task. In A. and B., markers with different letters are significantly different from one another (p ≤ .005 - .0001). In C.,^a p ≤ .005 vs rats at the 0 second delay, and^b p ≤ .001 & .004 vs rats at the 0 and 3 second delays respectively. Each marker represents group mean ± S.E.M.. n = 20 and 19 rats in the Vehicle or Risp 3.0 groups respectively.