Elsevier

Biological Psychiatry

Volume 69, Issue 12, 15 June 2011, Pages e89-e99
Biological Psychiatry

Review
Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks

https://doi.org/10.1016/j.biopsych.2011.01.027Get rights and content

The symptoms of attention-deficit/hyperactivity disorder (ADHD) involve impairments in prefrontal cortical top-down regulation of attention and behavior. All current pharmacological treatments for ADHD facilitate catecholamine transmission, and basic research suggests that these compounds have prominent actions in the prefrontal cortex (PFC). The dorsolateral PFC is especially sensitive to levels of norepinephrine and dopamine, whereby either too little or too much markedly impairs PFC function. Recent physiological studies have shown that norepinephrine strengthens PFC network connectivity and maintains persistent firing during a working memory task through stimulation of postsynaptic α2A-adrenoceptors on PFC neurons. Conversely, dopamine acts at D1 receptors to narrow spatial tuning, sculpting network inputs to decrease noise (i.e., stabilization of the representation). The stimulant medications and atomoxetine appear to enhance PFC function by indirectly increasing these catecholamine actions through blockade of norepinephrine and/or dopamine transporters. In contrast, guanfacine mimics the enhancing effects of norepinephrine at postsynaptic α2A-receptors in the PFC, strengthening network connectivity. Stronger PFC regulation of attention, behavior, and emotion likely contributes to the therapeutic effects of these medications for the treatment of ADHD.

Section snippets

Top-Down Regulation by Prefrontal Cortex

The PFC intelligently regulates our thoughts, actions, and emotions through extensive connections with other brain regions, including projections to the association cortices for the regulation of sensory processing (8) and extensive projections to the basal ganglia and cerebellum for the regulation of motor, cognitive, and emotional responses (9) (Figure 1). The PFC creates a mental sketch pad through networks of neurons that maintain information in the absence of environmental stimulation (10

The Key Role of Prefrontal Cortical Networks in Representational Knowledge

The PFC is able to represent information that is not currently in the environment through networks of pyramidal neurons that excite each other to maintain information in mind. The circuitry underlying representational knowledge in PFC has been most intensively studied in the visuospatial realm, in monkeys performing a spatial working memory task (Figure 2A). In this task, the monkey has to maintain the memory of a precise spatial location over a delay period before moving its eyes to the

The Strength of Network Connections Is Rapidly Altered by the Neurochemical Environment: Integrating Arousal and Cognition

The arousal pathways (e.g., norepinephrine, dopamine, acetylcholine, serotonin, histamine, and orexins) all project to the PFC, and it is likely that all influence PFC function (26). However, a long history of research on the catecholamines has advanced our knowledge of these mechanisms in particular. This research began with the landmark discovery that depletion of catecholamines from the dorsolateral PFC was as detrimental as ablation of the cortical tissue itself (4). It is now known that

The Underappreciated Role of Norepinephrine

Although much of the previous research on ADHD and PFC has focused on DA mechanisms, recent data indicate that NE mechanisms are just as important and may even have more utility for the development of medications because of distinct NE actions at adrenergic receptors. Norepinephrine has the highest affinity for α2 adrenergic receptors and lower affinity for α1 and β receptors (34). Therefore, the type of receptor engaged may be determined by the amount of NE release.

Data from studies of monkey

The Complex Roles of DA

It has long been appreciated that DA is essential to the working memory functions of the PFC (4). New research is now revealing the contribution of DA to orbital PFC functions as well, which appears to differ from serotonergic actions (96) (26). The current article focuses on DA actions in dorsolateral PFC during spatial working memory, given this has been best studied at the cellular level.

There are two families of DA receptors: the D1 (D1 or D5) and D2 (D2, D3, D4) families of receptors. The

Conclusions

There has been remarkable progress in our understanding of PFC circuits and their relevance to ADHD. Studies of catecholamine actions on dorsolateral PFC microcircuitry have revealed intricate and powerful mechanisms to regulate the strength of persistent neuronal firing and the degree of neuronal tuning. Given the complexity and precision of these mechanisms, it is not surprising that problems with PFC regulation are prevalent in many neuropsychiatric disorders. As NE and DA mediate the

References (140)

  • P.S. Goldman-Rakic

    Cellular basis of working memory

    Neuron

    (1995)
  • J.J. Buccafusco et al.

    A reversible model of the cognitive impairment associated with schizophrenia in monkeys: Potential therapeutic effects of two nicotinic acetylcholine receptor agonists

    Biochem Pharmacol

    (2009)
  • A.C. Roberts

    The importance of serotonin for orbitofrontal function

    Biol Psychiatry

    (2011)
  • G. Aston-Jones et al.

    Role of locus coeruleus in attention and behavioral flexibility

    Biol Psychiatry

    (1999)
  • J.M. Finlay et al.

    Increased dopamine and norepinephrine release in medial prefrontal cortex induced by acute and chronic stress: Effects of diazepam

    Neuroscience

    (1995)
  • B.-M. Li et al.

    Delayed-response deficit induced by local injection of the alpha 2-adrenergic antagonist yohimbine into the dorsolateral prefrontal cortex in young adult monkeys

    Behav Neural Biol

    (1994)
  • S.G. Birnbaum et al.

    A role for norepinephrine in stress-induced cognitive deficits: Alpha-1-adrenoceptor mediation in the prefrontal cortex

    Biol Psychiatry

    (1999)
  • B. Ramos et al.

    The beta-1 adrenergic antagonist, betaxolol, improves working memory performance in rats and monkeys

    Biol Psychiatry

    (2005)
  • N.J. Gamo et al.

    Methylphenidate and atomoxetine enhance prefrontal function through α2-adrenergic and dopamine D1 receptors

    J Am Acad Child Adolesc Psychiatry

    (2010)
  • Z.-M. Mao et al.

    Local infusion of an alpha-1 adrenergic agonist into the prefrontal cortex impairs spatial working memory performance in monkeys

    Biol Psychiatry

    (1999)
  • J. O'Neill et al.

    Effects of guanfacine on three forms of distraction in the aging macaque

    Life Sci

    (2000)
  • P. Jakala et al.

    Guanfacine, but not clonidine, improves planning and working memory performance in humans

    Neuropsychopharmacology

    (1999)
  • M.M. McClure et al.

    The effects of guanfacine on context processing abnormalities in schizotypal personality disorder

    Biol Psychiatry

    (2007)
  • A.F.T. Arnsten et al.

    The alpha-1 adrenergic agonist, cirazoline, impairs spatial working memory performance in aged monkeys

    Pharmacol Biochem Behav

    (1997)
  • A.F.T. Arnsten et al.

    Alpha-1 noradrenergic receptor stimulation impairs prefrontal cortical cognitive function

    Biol Psychiatry

    (1999)
  • C.O. Bondi et al.

    Beneficial effects of desipramine on cognitive function of chronically stressed rats are mediated by alpha1-adrenergic receptors in medial prefrontal cortex

    Prog Neuropsychopharmacol Biol Psychiatry

    (2010)
  • M. Wang et al.

    Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex

    Cell

    (2007)
  • B.-M. Li et al.

    Alpha-2 adrenergic modulation of prefrontal cortical neuronal activity related to spatial working memory in monkeys

    Neuropsychopharmacology

    (1999)
  • M. Wang et al.

    Enhanced visuomotor associative learning following stimulation of alpha 2A-adrenoceptors in the ventral prefrontal cortex in monkeys

    Brain Res

    (2004)
  • E.F. Coccaro et al.

    Corticolimbic function in impulsive aggressive behavior

    Biol Psychiatry

    (2011)
  • C.-L. Ma et al.

    Locomotor hyperactivity induced by blockade of prefrontal cortical alpha2-adrenoceptors in monkeys

    Biol Psychiatry

    (2005)
  • J.J.M. Barnes et al.

    The molecular genetics of executive function: Role of monoamine system genes

    Biol Psychiatry

    (2011)
  • C.M. Greene et al.

    Noradrenergic genotype predicts lapses in sustained attention

    Neuropsychologia

    (2009)
  • S.R. Chamberlain et al.

    Translational approaches to frontostriatal dysfunction in attention-deficit/hyperactivity disorder using a computerized neuropsychological battery

    Biol Psychiatry

    (2011)
  • C.W. Berridge et al.

    Methylphenidate preferentially increases catecholamine neurotransmission within the prefrontal cortex at low doses that enhance cognitive function

    Biol Psychiatry

    (2006)
  • C.W. Berridge et al.

    Psychostimulants as cognitive enhancers: The prefrontal cortex, catecholamines, and attention-deficit/hyperactivity disorder

    Biol Psychiatry

    (2011)
  • A.R. Aron et al.

    Methylphenidate improves response inhibition in adults with attention-deficit/hyperactivity disorder

    Biol Psychiatry

    (2003)
  • 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)
  • S.R. Chamberlain et al.

    Atomoxetine improved response inhibition in adults with attention deficit/hyperactivity disorder

    Biol Psychiatry

    (2007)
  • S.R. Chamberlain et al.

    Atomoxetine modulates right inferior frontal activation during inhibitory control: A pharmacological functional magnetic resonance imaging study

    Biol Psychiatry

    (2009)
  • J.N. Giedd et al.

    Anatomical brain magnetic resonance imaging of typically developing children and adolescents

    J Am Acad Child Adolesc Psychiatry

    (2009)
  • A.F. Arnsten

    Stress signaling pathways that impair prefrontal cortex structure and function

    Nat Rev Neurosci

    (2009)
  • T. Brozoski et al.

    Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey

    Science

    (1979)
  • A.C. Roberts et al.

    6-Hydroxydopamine lesions of the prefrontal cortex in monkeys enhance performance on an analog of the Wisconsin Card Sort Test: Possible interactions with subcortical dopamine

    J Neurosci

    (1994)
  • T.W. Robbins et al.

    Differential regulation of fronto-executive function by the monoamines and acetylcholine

    Cereb Cortex

    (2007)
  • J.M. Fuster

    The Prefrontal Cortex

    (2008)
  • P.S. Goldman-Rakic

    The prefrontal landscape: Implications of functional architecture for understanding human mentation and the central executive

    Philos Trans R Soc Lond B Biol Sci

    (1996)
  • S.L. Thompson-Schill et al.

    Effects of frontal lobe damage on interference effects in working memory

    Cogn Affect Behav Neurosci

    (2002)
  • T.J. Buschman et al.

    Top-down versus bottom-up control of attention in the prefrontal and posterior parietal cortices

    Science

    (2007)
  • A. Gazzaley et al.

    Functional interactions between prefrontal and visual association cortex contribute to top-down modulation of visual processing

    Cereb Cortex

    (2007)
  • Cited by (350)

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