Abstract
Methylphenidate (MPH), commonly known as Ritalin, is the most widely prescribed drug worldwide to treat patients with attention deficit disorders. Although MPH is thought to modulate catecholamine neurotransmission in the brain, it remains unclear how these neurochemical effects influence neuronal activity and lead to attentional enhancements. Studies in rodents overwhelmingly point to the lateral prefrontal cortex (LPFC) as a main site of action of MPH. To understand the mechanism of action of MPH in a primate brain, we recorded the responses of neuronal populations using chronic multielectrode arrays implanted in the caudal LPFC of two macaque monkeys while the animals performed an attention task (N = 2811 neuronal recordings). Over different recording sessions (N=55), we orally administered either various doses of MPH or a placebo to the animals. Behavioral analyses revealed positive effects of MPH on task performance at specific doses. However, analyses of individual neurons activity, noise correlations, and neuronal ensemble activity using machine learning algorithms revealed no effects of MPH. Our results suggest that the positive behavioral effects of MPH observed in primates (including humans) may not be mediated by changes in the activity of caudal LPFC neurons. MPH may enhance cognitive performance by modulating neuronal activity in other regions of the attentional network in the primate brain.
Significance Statement Methylphenidate (MPH), widely known as Ritalin, is the most prescribed drug to treat patients with attention deficits. Nonetheless, it is still unclear how and why the drug improves attention in humans. Studies in rodents point to the prefrontal cortex (PFC) as the main target of MPH. To validate these findings in primates, we trained macaque monkeys to perform an attention task while under various doses of MPH. We also chronically implanted multielectrode arrays in the posterior PFC of these monkeys to record neuronal ensemble activity during the task. Surprisingly, we found no effect of the drug on neuronal activity, even at cognitive-enhancing doses of MPH. The caudal prefrontal cortex might not be the site of action of MPH in the primate brain.
Footnotes
The authors report no conflict of interest.
Gouvernement du Canada | Canadian Institutes of Health Research (CIHR) [501100000024]
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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