The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex

Abstract

Psychostimulants are highly effective in the treatment of attention deficit hyperactivity disorder (ADHD). The clinical efficacy of these drugs is strongly linked to their ability to improve cognition dependent on the prefrontal cortex (PFC) and extended frontostriatal circuit. The procognitive actions of psychostimulants are only associated with low doses. Surprisingly, despite nearly 80 years of clinical use, the neurobiology of the procognitive actions of psychostimulants has only recently been systematically investigated. Findings from this research unambiguously demonstrate that the cognition-enhancing effects of psychostimulants involve the preferential elevation of catecholamines in the PFC and the subsequent activation of norepinephrine α2- and dopamine D1 receptors. In contrast, while the striatum is a critical participant in ‘PFC-dependent’ cognition, where examined, psychostimulant action within the striatum is not sufficient to enhance cognition. At doses that moderately exceed the clinical range, psychostimulants appear to improve PFC-dependent attentional processes at the expense of other PFC-dependent processes (e.g. working memory, response inhibition). This differential modulation of PFC-dependent processes across dose appears to be associated with the differential involvement of noradrenergic α2 vs. α1 receptors. Collectively, this evidence indicates that at low, clinically-relevant doses, psychostimulants are devoid of the behavioral and neurochemical actions that define this class of drugs and instead act largely as cognitive enhancers (improving PFC-dependent function). This information has potentially important clinical implications as well as relevance for public health policy regarding the widespread clinical use of psychostimulants and for the development of novel pharmacological treatments for ADHD and other conditions associated with PFC dysregulation.

Dopamine Does Double Duty in Motivating Cognitive Effort

“…However, we think that, for most operating regimes, PFC DA tone is unlikely to yield destabilization. As noted in a recent review (Spencer et al, 2015), intra-PFC injections of methylphenidate in rats, boosting DA tone, do not impair working memory at concentrations that are 16- to 32-fold higher than clinically relevant methylphenidate doses. This stands in contrast to the observation that systemic administration of methylphenidate can impair working memory at 4-fold concentrations higher than clinical doses.…”

Catecholamine mechanisms in the prefrontal cortex: proven strategies for enhancing higher cognitive function

“…Consistent with this, the working memory improving effects of psychostimulants and SNRIs, are prevented with systemically or intra-PFC infusion of a2 and D1 antagonists [53,55,56]. Combined, the available evidence indicates that the ability of psychostimulants and other ADHD related treatments to improve PFC-dependent cognition involves moderate increases in DA D1 and/or NE a2 receptor activation in the PFC that strengthens neuronal processing of context-relevant and task-relevant information ( Figure 2).…”

Discordant reporting of nonmedical amphetamine use among Adderall-using high school seniors in the US

“…In 2015, two-thirds (65.7%) of any past-year use of prescription stimulants among Americans aged ≥12 involved amphetamine (Hughes et al, 2016). Adderall, a commercial name for a combination of amphetamine salts, has been linked to enhanced cognitive function and academic performance, which in part, has led to nonmedical use among high school and college students (Cassidy et al, 2012; Spencer et al, 2015). In 2015, an estimated 5.3 million Americans aged ≥12 engaged in such nonmedical use of amphetamine-like prescription stimulants; of these, 4.8 million used amphetamine, corresponding to approximately 1.8% of the population (Hughes et al, 2016).…”