Abstract
Psychostimulants, such as amphetamine, are widely used to treat attentional deficits. In humans, response to dopaminergic medications is complex with improvement often dependent on baseline performance. Our goal was to determine if attention in rats could be improved by low dose amphetamine in a baseline-dependent manner by examining the relationship between task performance, drug response and monoamine levels in corticostriatal tissue. Firstly, rats performed a signal detection task with varying signal durations before administration of saline, 0.1 or 0.25 mg/kg amphetamine. Following 0.1 mg/kg amphetamine, accuracy in poor performing individuals increased to that of high performing rats. Furthermore, baseline accuracy correlated with the magnitude of improvement after amphetamine. Secondly, neurochemical analysis of monoamine content and gene expression levels in the prefrontal cortex (PFC) and dorsal striatum (CPU) was conducted. CPU homovanillic acid and 5-hydroxyindoleacetic acid levels were increased in poor performers with a significant correlation between the expression of the dopamine transporter gene and baseline accuracy. No changes were found in the PFC. These results indicated poor performance was associated with greater response to amphetamine and altered DA and 5-HT neurotransmitter systems in CPU. These results suggest striatal monoamine function may be fundamental to explaining individual differences in psychostimulant response.
Highlights
Altered catecholamine functioning in cortical and striatal brain regions have been implicated in a number of neuropsychiatric disorders, such as schizophrenia, Parkinson’s disease and attention deficit hyperactivity disorder (ADHD)
It was found that the procognitive effects of low dose amphetamine were dependent on baseline performance and drug response was compared between low and high performance groups[24]
The major findings from this study were that (1) attention was improved in low performing animals using a low dose of amphetamine; (2) baseline performance correlated with the magnitude of improvement after amphetamine; and (3) homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) levels were higher in low performing rats, while expression of dopamine transporter (DAT) was reduced in the striatum and the levels correlated with baseline performance
Summary
Altered catecholamine functioning in cortical and striatal brain regions have been implicated in a number of neuropsychiatric disorders, such as schizophrenia, Parkinson’s disease and attention deficit hyperactivity disorder (ADHD). Despite being one of the mainstream treatment for improving attentional deficits in humans, low doses of amphetamine have only improved attention in a handful of preclinical studies[12, 15,16,17] This may be due to species-specific differences in drug metabolism or because the relationship between cognitive performance and catecholamine function is very complex. Individual variability in Sprague-Dawley rats has been used to demonstrate the relationship between working memory performance and response to L-745,870, a selective D4 antagonist in rats[22]; as well as between working memory performance and locomotor response to amphetamine[20] These findings support the hypothesis that individual differences in baseline functioning and response to dopaminergic agents are linked. The aim of this study was to determine if attentional performance in rats could be improved with low dose amphetamine, and to examine the relationship between task performance, drug response and catecholamine levels in corticostriatal tissue. Our results suggest that rodents can be used to investigate amphetamine-induced improvement in attention and that striatal dopaminergic and serotonergic systems are associated with differences in attentional performance
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