ReviewThe Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex
Section snippets
Clinically Relevant Doses of Psychostimulants Elevate Catecholamine Signaling Preferentially in the PFC
The two most commonly used psychostimulants in the treatment of ADHD are methylphenidate (MPH) (e.g., Ritalin) and amphetamine (e.g., Adderall). At behaviorally activating doses, these drugs potently increase extracellular levels of norepinephrine (NE) and dopamine (DA) throughout the brain, largely by blocking NE and DA reuptake (27, 28). Some psychostimulants, particularly amphetamine, actively stimulate DA efflux through the DA transporter (29). Although amphetamine can also stimulate NE
Potential Mechanisms Underlying the Preferential Sensitivity of PFC Catecholamines
The above-described studies fail to identify the circuit mechanisms associated with the preferential sensitivity of PFC catecholamines. Recent studies using reverse microdialysis demonstrate that when infused in low concentrations, MPH elicits significantly larger increases in extracellular NE and DA in the PFC relative to the medial septum or NAcc (43) (Figure 3). This selectivity for the PFC disappeared with higher concentrations of MPH, similar to that seen with systemic administration (24,
Do The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action within the PFC?
Though correlative in nature, the neurochemical effects of low-dose psychostimulants reviewed above suggest the hypothesis that the PFC is an important site of action in the cognition-enhancing properties of these drugs. As in primates, the rat medial PFC is functionally and anatomically heterogeneous, with the dorsomedial PFC (dmPFC) (i.e., dorsal anterior cingulate, dorsal prelimbic PFC) associated with flexible cognitive function and the ventromedial PFC (i.e., infralimbic PFC, ventral
Psychostimulant Action Outside the PFC: Striatum
The above reviewed information unambiguously demonstrates the PFC is a key region for the cognition-enhancing/therapeutic effects of psychostimulants. Nonetheless, the PFC does not act in isolation to support higher cognitive function, representing one node in a broader corticothalamocortical circuit. As part of this, the PFC extends topographically organized projections to the striatum (61, 62), a region that plays a prominent role in cognitive processes historically associated with the PFC,
Clinically Relevant Doses of Psychostimulants Strengthen Neuronal Signaling in the PFC
A number of imaging studies indicate that cognition-enhancing doses of psychostimulants normalize ADHD-related hypoactivity within frontostriatal circuitry (12, 68, 69, 70). However, additional evidence indicates that clinically relevant doses of psychostimulants exert a more complex pattern of actions on frontostriatal activity that are task-, region-, and hemisphere-dependent (13, 71, 72, 73, 74). Currently, there exists only limited information regarding the electrophysiological mechanisms
Receptor Mechanisms in the PFC: NE α2 and DA D1 Receptors
DA and NE exert an inverted-U shaped facilitation of both PFC dependent working memory and PFC neuronal signaling. In the case of DA, these actions involve inverted-U shaped modulatory actions of D1 receptors (78). For NE, high-affinity postsynaptic α2 receptors improve, whereas lower affinity α1 receptors engaged at higher rates of NE release impair, working memory and PFC neuronal signaling (79). Importantly, α2-agonists are efficacious in the treatment of ADHD and improve PFC-dependent
Differing Dose-Response Curves Across Cognitive Tasks Reflect Differing Noradrenergic Receptor Action
In 1977, Sprague and Sleator (93) reported that in ADHD children, MPH elicited a narrow inverted-U shaped facilitation of performance in a cognition/learning task, while classroom behavior was improved across a wider dose range. However, subsequent studies generally failed to observe differential sensitivity to MPH dose across a range of cognitive tasks versus overt behavior in ADHD patients (94, 95, 96). Importantly, Sprague and Sleator (93) used a memory task that involved short delays
Implications for Divergent Dose-Response Curves Across PFC-Dependent Processes
Preclinically, the differential dose sensitivity of PFC-dependent tasks to psychostimulants suggests that not all PFC-dependent tasks are well suited for ADHD-focused drug discovery programs. Extensive evidence demonstrates that the pharmacology of working memory mirrors the pharmacology of ADHD: all approved ADHD-related drugs, including α2 agonists (105), low-dose psychostimulants (5, 25), and selective NE reuptake blockers (e.g., atomoxetine) (34) improve working memory. For
Summary and Implications
Low-dose psychostimulants are the first-line treatment for ADHD. At clinically relevant doses, these drugs improve frontostriatal cognitive function in ADHD patients and healthy individuals. The procognitive and behavioral calming actions of psychostimulants are in stark contrast to the behaviorally activating and cognition-impairing effects seen with higher doses. For much of the history of psychostimulant treatment of ADHD, there has been an emphasis on the possible involvement of striatal DA
Acknowledgments and Disclosures
This work was supported by Public Health Service Grants MH098631, MH081843, and DA000389; the National Science Foundation (NSF 0918555); the Wisconsin Institutes of Discovery; and the University of Wisconsin Graduate School. Mr. Spencer and Dr. Berridge report no biomedical financial interests or potential conflicts of interest. Dr. Devilbiss is the founder of NexStep Biomarkers, LLC. NexStep Biomarkers had no role in study design, data collection and analysis, decision to publish, or
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