Receptor and circuit mechanisms underlying differential procognitive actions of psychostimulants

Psychostimulants, including methylphenidate (MPH), improve cognitive processes dependent on the prefrontal cortex (PFC) and extended frontostriatal circuitry. In both humans and animals, systemic MPH improves certain cognitive processes, such as working memory, in a narrow inverted-U-shaped manner. In contrast, other processes, including attention-related, are improved over a broader/right-shifted dose range. The current studies sought to elucidate the potential circuit and receptor mechanisms underlying the divergent dose-dependent procognitive effects of psychostimulants. We first observed that, as with working memory, although sustained attention testing was highly dependent on multiple frontostriatal regions, only MPH infusion into the dorsomedial PFC improved task performance. Importantly, the dose-response curve for this action was right-shifted relative to working memory, as seen with systemic administration. Additional studies examined the receptor mechanisms within the PFC associated with the procognitive actions of MPH across working memory and sustained attention tasks. We observed that PFC alpha 2 and D1 receptors contributed to the beneficial effects of MPH across both cognitive tasks. However, alpha 1 receptors only contributed to MPH-induced improvement in sustained attention. Moreover, activation of PFC alpha 1 receptors was sufficient to improve sustained attention. This latter action contrasts with the impairing actions of PFC alpha 1 receptors reported previously for working memory. These results provide further evidence for a prominent role of the PFC in the procognitive actions of MPH and demonstrate the divergent dose sensitivity across cognitive processes aligns with the differential involvement of PFC alpha 1 receptors.