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The Cognition-Enhancing Effects of Psychostimulants Involve Direct Action in the Prefrontal Cortex
Open accessAbstract
Psychostimulants are highly effective in the treatment of attention-deficit/hyperactivity disorder. 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 versus 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 pharmacologic treatments for attention-deficit/hyperactivity disorder and other conditions associated with PFC dysregulation.
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“DA acts as an inverted U-shaped pattern to cognitive performance. As is reported, too lower or higher DA level elicited by clinically-inappropriate doses of d-amphetamine impairs cognition (12).”
From Effects of Lisdexamfetamine, a Prodrug of D-Amphetamine, on Locomotion, Spatial Cognitive Processing and Neurochemical Profiles in Rats: A Comparison With Immediate-Release Amphetamine (2022) · cites this paper as [12]
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“The cognitive-enhancing effects of amphetamine occur through the dopaminergic transmission activation which, in turn, is mediated by both D1 dopamine receptors and α2-adrenoceptors in postsynaptic neurons in PFC [188].”
From Molecular Characterisation of the Mechanism of Action of Stimulant Drugs Lisdexamfetamine and Methylphenidate on ADHD Neurobiology: A Review (2022) · cites this paper as [188]
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Metadata
- Authors
- Spencer, R. C., Devilbiss, D. M., & Berridge, C. W.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Berridge, Craig W.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2015-06
- Volume
- 77
- Issue
- 11
- Pages
- 940-950
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4377121
- OpenAlex
- W2080244900
- Cited by
- 164
- References
- 108
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 8 · 2023: 15 · 2022: 18 · 2021: 22 · 2020: 9 · 2019: 20 · 2018: 13 · 2017: 17 · 2016: 14 · 2015: 8
- FWCI
- 1.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Rowan Digitals Works (Rowan University) (submittedVersion, cc-by-nc-nd)
- Funders
- Public Health Service (MH098631, MH081843, DA000389)
- National Science Foundation (NSF 0918555)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Social Sciences › Arts and Humanities › Philosophy › Neuroethics, Human Enhancement, Biomedical Innovations
- Keywords
- psychostimulants, cognitive enhancement, prefrontal cortex, attention deficit hyperactivity disorder, catecholamines, dopamine D1 receptor, striatum, frontostriatal circuits, dose-dependent effects, working memory, response inhibition, attention
- MeSH terms
- Central Nervous System Stimulants, Animals, Cognition, Humans, Prefrontal Cortex
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