Research reportThe effects of amphetamine on working memory and locomotor activity in adult rats administered risperidone early in life
Introduction
Antipsychotic drugs are used in the treatment of pediatric psychiatric disorders, such as attention deficit hyperactivity disorder, disruptive behavioral disorder, and autism [[1], [2], [3]]. Boys are more likely to receive these drugs than girls [2], and the most widely prescribed antipsychotic drug to children in the United States is risperidone [4]. Drugs such as risperidone produce their clinical effects via the blockade of dopamine and serotonin receptors in various regions of the forebrain [5]. One concern regarding the prolonged use of these drugs in children is that activity at these receptors may be critical for postnatal brain development, and that the extended receptor blockade imposed by drug treatment early in life may undermine behavioral and cognitive competence during adulthood. In rodents, some neurotransmitters receptors are not uniformly mature or expressed across early development [6,7], but early-life manipulations directed at specific dopamine or serotonin receptors can lead to a variety of neural and behavioral changes during adulthood [e.g., [8], [9], [10], [11], [12]].
Recent studies in young rats have shown that risperidone administration at ages analogous to early childhood through early adolescence in humans leads to locomotor hyperactivity later in life [[13], [14], [15]]. This outcome raises the question as to whether early-life risperidone administration modifies other behavioral and cognitive functions linked to brain regions targeted by risperidone. For example, the frontal cortex has been implicated in a myriad of behaviors related to impulse control, decision-making, and working memory [16], and appears to be a primary site of risperidone’s action in the brain (see Kuroki, Nagao, & Nakahara [17] for review). Daily risperidone administration for 3–4 weeks after weaning in rats modifies neurotransmitter receptor density in the frontal cortex, including increases in dopamine D2, serotonin 5HT1A, and glutamatergic AMPA receptors, and decreases in D1 and 5HT2A receptors [[18], [19], [20], [21]]. If these changes in receptor number persist into adulthood, or simply alter the subsequent course of frontal cortical development, they could possibly weaken cognitive functions such as working memory.
In adult rats, the effects of chronic risperidone administration on working memory have been mixed, with results demonstrating positive [22], negative [23], and no effects [24]. To date, no study has assessed the effects of developmental risperidone administration on working memory in rats, although Frost and colleagues [25] reported that developmental olanzapine administration disrupts performance in a delayed non-matching-to-sample task during adulthood. A study by Mandell, Unis, and Sackett [26] compared the effects of early-life risperidone and quetiapine administration on perseverative errors made within a trial set by juvenile macaque monkeys. While performance was not significantly affected during an eight-week period of drug administration, risperidone-treated animals made more perseverative errors over a four-week period following the cessation of drug administration. Whether this effect persisted beyond this period and into adulthood was not determined.
Even if developmental risperidone administration does not affect working memory in rats, it could alter the sensitivity of forebrain systems that subserve this function to disruption. Given the affinity of risperidone for dopamine and serotonin receptors, it merits consideration that drug challenges known to produce memory deficits via their actions on dopamine and serotonin may have a greater impact on adult rats administered risperidone early in life. For example, acute administration of d-amphetamine, a psychostimulant that increases extracellular dopamine and norepinephrine levels, decreases the percentage of correct choices in an operant-based, delayed non-matching-to-sample task [27]. Our lab has recently reported that rats administered risperidone early in life are more sensitive to the locomotor-activating effects of amphetamine [15]. Whether adult rats administered risperidone early in life are more sensitive to the memory-impairing effects of amphetamine remains unknown.
One of the goals of this study was to characterize the effects of early-life, subcutaneous (sc) administration of risperidone on working memory during adulthood in rats. Working memory was assessed in an operant-based, delayed non-matching-to-sample task using two different sets of delay intervals (0–8 and 0–24 second range). Following the assessment of working memory at these intervals, performance was then measured using the latter delay intervals after acute administration of two doses (0.75 and 1.25 mg/kg, sc) of amphetamine. Locomotor activity and locomotor responses to a single dose (1.0 mg/kg, sc) of amphetamine were measured prior to memory testing. These latter experiments were included to confirm our previous results regarding the effects of early-life risperidone on spontaneous and drug-induced locomotor activity, and to consider the possibility of sex differences in these effects.
Section snippets
Animals and housing
Forty Long-Evans rats were used with 18 females and 22 males. These rats were derived from five litters born at our animal facility. Litters were culled on postnatal day 8 to eight total pups comprised of three-four pups of each sex (based on the availability of female and male pups from each litter). Rats were weaned on postnatal day 21. Upon weaning, rats were housed two per cage with continuous access to food and water, except where noted for the working memory testing. The lights in the
Results
Rats were tested for locomotor activity once a day for one hour on four consecutive days beginning on postnatal day 54. There was a significant main effect of testing day, F(3, 108) = 11.2, p < .0001, with declines in activity seen mainly on the last three days of testing relative to the first test day. Since there were no interactions between sex or risperidone with test day, the remaining analyses focused on the main effects of the former two variables on the hourly activity averaged across
Discussion
Rats administered risperidone early in life demonstrated modest yet significant changes in working memory as adults. When working memory was tested using shorter delays during the initial test sessions, the risperidone group performed the same as the vehicle group. However, when longer delays were built into the testing, the risperidone-administered rats made significantly fewer correct choices during the no delay trials. It is not obvious why these rats performed worse during the no delay
Conflict of interest
All authors declare no conflict of interest.
Acknowledgement
This work was supported by the National Institute of Health (grant numbers P20GM103436, R15DA041708). This funding source had no other role in the research other than funding.
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