Receptor and circuit mechanisms underlying differential procognitive actions of psychostimulants

Abstract

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 α2 and D1 receptors contributed to the beneficial effects of MPH across both cognitive tasks. However, α1 receptors only contributed to MPH-induced improvement in sustained attention. Moreover, activation of PFC α1 receptors was sufficient to improve sustained attention. This latter action contrasts with the impairing actions of PFC α1 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 α1 receptors.

Pharmacological evidence for the implication of noradrenaline in effort

“…Second, pharmacological manipulations of the NA system strongly affect performance in tasks requiring a high level of executive control [ 50 – 53 ] or attentional set-shifting [ 54 – 56 ]. These data are directly in line with the key action of NA on executive functions and its neural substrate in the prefrontal cortex [ 57 – 59 ]. Intuitively, these data could be interpreted in terms of “mental effort,” with the intuition that here effort would affect the trade-off between difficulty and performance in the cognitive rather than physical domain.…”

Locus Coeruleus Norepinephrine in Learned Behavior: Anatomical Modularity and Spatiotemporal Integration in Targets

“…This depolarization in the presence of NE normally leads to an increase in firing rate of neurons and ultimately, increased sensory sensitivity ( Polack et al, 2013 ). In prefrontal cortex regions such as the anterior cingulate cortex and limbic cortex, local manipulation of NE activity influences sustained attention ( Berridge et al, 2012 ; Spencer and Berridge, 2019 ), memory ( Berridge et al, 2012 ; Spencer and Berridge, 2019 ), decision making, and task acquisition ( Tait et al, 2007 ; Tervo et al, 2014 ; Cope et al, 2019 ; Joshi and Gold, 2019 ). NE release in the anterior cingulate cortex promotes exploration and behavioral variation ( Tervo et al, 2014 ).…”

Amphetamine promotes cortical Up state: Role of adrenergic receptors

“…Recent studies show that blockade of PFC α 1 receptor also attenuates cocaine-primed reinstatement 2 and foster extinction of amphetamine-induced conditioned place preference. 3 PFC α 1 receptor activation, on the other hand, improves sustained attention, 4 excites PFC neurons, 5 and enhances PFC glutamatemediated synaptic transmission. [6][7][8][9][10] In this study, we examined the effect of d-amphetamine on the slow oscillatory activities of PFC neurons and the associated Up and Down states.…”