Abstract
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.
Keywords
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Article info
Publication history
Published online: September 25, 2014
Accepted:
September 18,
2014
Received in revised form:
September 16,
2014
Received:
May 29,
2014
Identification
Copyright
© 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
