Elsevier

Biological Psychiatry

Volume 77, Issue 11, 1 June 2015, Pages 940-950
Biological Psychiatry

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

https://doi.org/10.1016/j.biopsych.2014.09.013Get rights and content

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.

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

References (108)

  • B. Meyers et al.

    In vitro binding assays using (3)H nisoxetine and (3)H WIN 35,428 reveal selective effects of gonadectomy and hormone replacement in adult male rats on norepinephrine but not dopamine transporter sites in the cerebral cortex

    Neuroscience

    (2009)
  • B. Giros et al.

    Delineation of discrete domains for substrate, cocaine, and tricyclic antidepressant interactions using chimeric dopamine-norepinephrine transporters

    J Biol Chem

    (1994)
  • H. Gu et al.

    Stable expression of biogenic amine transporters reveals differences in inhibitor sensitivity, kinetics, and ion dependence

    J Biol Chem

    (1994)
  • F.P. Bymaster et al.

    Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: A potential mechanism for efficacy in attention deficit/hyperactivity disorder

    Neuropsychopharmacology

    (2002)
  • J.W. Dalley et al.

    Prefrontal executive and cognitive functions in rodents: Neural and neurochemical substrates

    Neurosci Biobehav Rev

    (2004)
  • R.C. Spencer et al.

    Psychostimulants act within the prefrontal cortex to improve cognitive function

    Biol Psychiatry

    (2012)
  • A. Armario

    Activation of the hypothalamic-pituitary-adrenal axis by addictive drugs: different pathways, common outcome

    Trends Pharmacol Sci

    (2010)
  • A. Smith et al.

    Neurofunctional effects of methylphenidate and atomoxetine in boys with attention-deficit/hyperactivity disorder during time discrimination

    Biol Psychiatry

    (2013)
  • K. Rubia et al.

    Methylphenidate normalises activation and functional connectivity deficits in attention and motivation networks in medication-naive children with ADHD during a rewarded continuous performance task

    Neuropharmacology

    (2009)
  • A.F. Marquand et al.

    Dissociable effects of methylphenidate, atomoxetine and placebo on regional cerebral blood flow in healthy volunteers at rest: A multi-class pattern recognition approach

    Neuroimage

    (2012)
  • A.M. Pauls et al.

    Methylphenidate effects on prefrontal functioning during attentional-capture and response inhibition

    Biol Psychiatry

    (2012)
  • L. Clark et al.

    Association between response inhibition and working memory in adult ADHD: A link to right frontal cortex pathology?

    Biol Psychiatry

    (2007)
  • R.D. Hunt et al.

    Clonidine benefits children with attention deficit disorder and hyperactivity: Report of a double-blind placebo-crossover therapeutic trial

    J Am Acad Child Psychiatry

    (1985)
  • H. Tanila et al.

    The effects of prefrontal intracortical microinjections of an alpha-2 agonist, alpha-2 antagonist and lidocaine on the delayed alternation performance of aged rats

    Brain Res Bull

    (1996)
  • Y. Wang et al.

    alpha2-Adrenoceptor regulates the spontaneous and the GABA/glutamate modulated firing activity of the rat medial prefrontal cortex pyramidal neurons

    Neuroscience

    (2011)
  • M.V. Solanto

    Neuropsychopharmacological mechanisms of stimulant drug action in attention-deficit hyperactivity disorder: A review and integration

    Behav Brain Res

    (1998)
  • M.D. Rapport et al.

    Psychostimulant effects on learning and cognitive function: Findings and implications for children with attention deficit hyperactivity disorder

    Clin Psychol Rev

    (1991)
  • C. Berridge et al.

    Differential sensitivity to psychostimulants across prefrontal cognitive tasks: Differential involvement of noradrenergic α1- vs. α2-receptors

    Biol Psychiatry

    (2012)
  • M.D. Lapiz et al.

    Noradrenergic modulation of cognitive function in rat medial prefrontal cortex as measured by attentional set shifting capability

    Neuroscience

    (2006)
  • D.S. Segal

    Behavioral and neurochemical correlates of repeated d-amphetamine administration

    Adv Biochem Psychopharmacol

    (1975)
  • J. McGaughy et al.

    Behavioral vigilance in rats: Task validation and effects of age, amphetamine, and benzodiazepine receptor ligands

    Psychopharmacology (Berl)

    (1995)
  • C.W. Berridge et al.

    Relationship between low-dose amphetamine-induced arousal and extracellular norepinephrine and dopamine levels within prefrontal cortex

    Synapse

    (2002)
  • A.F. Arnsten et al.

    Methylphenidate improves prefrontal cortical cognitive function through alpha2 adrenoceptor and dopamine D1 receptor actions: Relevance to therapeutic effects in attention deficit hyperactivity disorder

    Behav Brain Funct

    (2005)
  • C. Bradley

    The behavior of children receiving benzadrine

    Am J Psychiatry

    (1937)
  • L.L. Greenhill

    Clinical effects of stimulant medication in ADHD

  • R.M. Scheffler et al.

    Positive association between attention-deficit/ hyperactivity disorder medication use and academic achievement during elementary school

    Pediatrics

    (2009)
  • J.L. Rapoport et al.

    Dextroamphetamine. Its cognitive and behavioral effects in normal and hyperactive boys and normal men

    Arch Gen Psychiatry

    (1980)
  • C.J. Vaidya et al.

    Selective effects of methylphenidate in attention deficit hyperactivity disorder: A functional magnetic resonance study

    Proc Natl Acad Sci U S A

    (1998)
  • M.A. Mehta et al.

    Methylphenidate enhances working memory by modulating discrete frontal and parietal lobe regions in the human brain

    J Neurosci

    (2000)
  • J.L. Rapoport et al.

    Responses to methylphenidate in attention-deficit/hyperactivity disorder and normal children: Update 2002

    J Atten Disord

    (2002)
  • R. Elliott et al.

    Effects of methylphenidate on spatial working memory and planning in healthy young adults

    Psychopharmacology (Berl)

    (1997)
  • J. Setlik et al.

    Adolescent prescription ADHD medication abuse is rising along with prescriptions for these medications

    Pediatrics

    (2009)
  • S.E. McCabe et al.

    Non-medical use of prescription stimulants among US college students: Prevalence and correlates from a national survey

    Addiction

    (2005)
  • B. Maher

    Poll results: Look who׳s doping

    Nature

    (2008)
  • R.A. Barkley

    Attention-deficit/hyperactivity disorder, self-regulation, and time: Toward a more comprehensive theory

    J Dev Behav Pediatr

    (1997)
  • F.X. Castellanos et al.

    Neuroscience of attention-deficit/hyperactivity disorder: The search for endophenotypes

    Nat Rev Neurosci

    (2002)
  • B.J. Casey et al.

    Frontostriatal connectivity and its role in cognitive control in parent-child dyads with ADHD

    Am J Psychiatry

    (2007)
  • J. Swanson et al.

    Pharmacokinetic and pharmacodynamic properties of methylphenidate in humans

  • A.F. Arnsten

    Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: An important role for prefrontal cortex dysfunction

    CNS Drugs

    (2009)
  • R. Kuczenski et al.

    Regional norepinephrine response to amphetamine using dialysis: Comparison with caudate dopamine

    Synapse

    (1992)
  • Cited by (0)

    View full text