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Dysfunction of the prefrontal cortex
(PFC) is a fundamental component of attention-deficit/hyperactivity disorder
(ADHD). The PFC uses working memory to intelligently guide behavior, inhibiting
inappropriate impulses or distractions and allowing us to plan and organize
effectively (see previous column). Individuals with ADHD are consistently
impaired on tests of frontal lobe function, and both structural and functional
imaging studies have shown evidence of altered PFC function in individuals
with ADHD. In particular, the right PFC has been shown to be consistently
smaller in ADHD subjects than in age-matched controls, and the inability
to suppress responses to salient but irrelevant stimuli correlates with
reduced volume of the right PFC (Casey et al., 1997).
The cognitive functioning of the PFC
is modulated in a critical manner by the neuromodulators norepinephrine
(NE) and dopamine (DA). Intriguingly, a recent positron emission tomography
study showed reduced fluorodopa binding in the PFC of adults with ADHD,
indicative of altered NE and/or DA transmission in the PFC in this disorder
(Ernst et al., 1998). Although most previous research has focused on DA
mechanisms, NE influences on PFC function are just as powerful. Indeed,
as recent research suggests that low doses of the ADHD medication methylphenidate
(Ritalint) preferentially release NE in rat brain, NE mechanisms may be
particularly relevant to our understanding of ADHD. This column will review
the evidence that NE has an essential beneficial influence on the working
memory and attention functions of the PFC through actions at postsynaptic,
a2A-noradrenergic receptors, while
very high levels of NE release appear to engage a1-noradrenergic
receptors and impair PFC functions.
NE has been associated with attention
regulation for many years. NE cells of the locus ceruleus increase their
firing in response to behaviorally relevant stimuli. Selective depletion
of NE in the forebrain makes animals more distractible. At least some
of these behavioral changes are likely due to altered NE in the PFC. Either
global depletion of catecholamines or depletion restricted to the PFC
impairs working memory and attention regulation, while having little effect
on basic visual discrimination and associative abilities.
Anatomical studies have documented
the NE innervation of the PFC in rodents, monkeys, and humans. NE axons
from cells of the locus ceruleus terminate throughout the PFC with moderate
density. The a- and b-noradrenergic
receptor subtypes have been observed in the PFC, and the a2A-noradrenergic
receptor has been localized both presynaptically and postsynaptically
in the primate PFC. Although previous research focused on presynaptic
a2-receptors ("autoreceptors"
that decrease NE release), it is now appreciated that the vast majority
of a2-receptors in the brain are
localized postsynaptic to NE cells. In the monkey PFC, a2A-receptor
immunoreactivity has been documented over the postsynaptic thickening
of dendritic spines of pyramidal cells, demonstrating an anatomical substrate
for postsynaptic actions.
a2-Noradrenergic
agonists such as clonidine, guanfacine, and meditomidine have been shown
to improve a variety of cognitive functions subserved by the PFC in rodents,
monkeys, and humans (Jakala et al., 1999). Systemic administration of
these compounds can enhance performance of working memory tasks, response
inhibition, and planning, particularly under distracting conditions. These
improvements are blocked by cotreatment with a2-antagonists,
consistent with actions at a2-receptors.
In contrast, a2-agonists have little
effect or actually impair performance of tasks that depend on posterior
cortices or subcortical structures, indicating functional specificity.
a2-Agonists are particularly potent
in enhancing PFC functions in subjects with catecholamine depletion due
to either experimental manipulations (e.g., the neurotoxin 6-OHDA or reserpine)
or natural conditions (e.g., aging, vitamin B deficiency in Korsakoff
amnesia). The finding that a2-agonists
become more, rather than less, efficacious in subjects with catecholamine
depletion is consistent with drug actions at postsynaptic a2-receptors.
Three a2-receptor
subtypes have been identified in humans: the A, B, and C subtypes. Pharmacological
profiles suggest that the a2A-subtype
underlies the PFC-enhancing effects of a2-agonists.
Thus agonists such as guanfacine, which are relatively selective for the
a2A-subtype, are able to improve
PFC function with fewer side effects than nonselective agonists such as
clonidine (Arnsten, 1998). Recent studies in mice with a mutation of the
a2A-receptor (a "functional
knockout") support this hypothesis: guanfacine improves the working
memory performance of wild type mice but has no effect in mice with a
mutation of the a2A-receptor (reviewed
by Arnsten, 2000). In contrast, a2-agonists remain effective in mice with
a knockout of the a2C-subtype. Work
with the a2B-knockout remains to
be done. Thus, studies to date have focused on the importance of the a2A-receptor
for PFC function.
Evidence suggests that a2-agonists
act directly in the PFC to enhance working memory function. The beneficial
effects of a2-agonists disappear
in subjects with PFC ablations, suggesting that the PFC is the substrate
for drug actions. Consistent with this idea, systemic administration of
guanfacine or clonidine has been shown to enhance regional cerebral blood
flow in the PFC of both human and nonhuman primates performing PFC tasks.
For example, Figure
1 shows the areas of enhanced
regional cerebral blood flow in the dorsolateral PFC of a monkey performing
a spatial working memory task. Lesions of this same area markedly impair
performance of this task.
More direct evidence for PFC actions
comes from animal studies in which the drug is infused directly into the
PFC. Infusions of guanfacine into the monkey dorsolateral PFC produce
a delay-related improvement in working memory performance. Similarly,
infusion of meditomidine into the PFC of aged rats improves working memory
as tested by the delayed alternation task. Conversely, infusion of the
a2-antagonist, yohimbine, into the
PFC of monkeys produces a marked, delay-related impairment in working
memory performance. These results indicate that endogenous NE stimulation
of a2-receptors in the PFC has a
critical influence on behavioral regulation. Infusions of a1-
or b-adrenergic antagonists were without effect
on performance, highlighting the importance of a2-receptors
to PFC function. Recent electrophysiological studies have shown that iontophoretic
application of yohimbine onto PFC cells in monkeys performing a working
memory task reduces delay-related firing of PFC neurons, the cellular
measure of working memory (Li et al., 1999). Conversely, either iontophoretic
or systemic administration of an a2-agonist
enhances delay-related activity. Thus, a2-receptor
stimulation is critical for PFC function at both the cellular and behavioral
level.
In contrast to the marked beneficial
effects of a2-receptor stimulation
on PFC functions, high levels of a1-noradrenergic
receptor stimulation impair PFC function (reviewed by Arnsten, 2000).
These detrimental actions appear to come into play under conditions of
very high NE release, e.g., during uncontrollable stress. In this regard,
it is of interest that NE has much lower affinity for a1-receptors than
for a2-receptors, suggesting that
high levels of NE release may be needed to significantly engage detrimental
a1 mechanisms. Administration of a2-agonists
can restore PFC cognitive function in stressed subjects with very high
levels of catecholamine release, suggesting that both pre- and postsynaptic
a2-receptors can contribute to beneficial
effects depending upon the state of the subject. Current research is exploring
the second-messenger mechanisms underlying the detrimental effects of
a1-receptor stimulation. Evidence
to date suggests that a1-receptor
stimulation impairs PFC function through activation of the phosphatidylinositol/protein
kinase C intracellular signaling pathway. It is intriguing that overactivity
of this intracellular pathway has been linked to mania, a disorder that
shares some similarities to the symptoms of ADHD.
In summary, research in animals demonstrates
that either too little a2-receptor
stimulation or too much a1-receptor stimulation can impair PFC cognitive
function. These findings suggest that altered NE transmission could contribute
to symptoms of ADHD. For example, mutations in the synthetic enzymes for
NE or in a2A-receptors could lead
to insufficient a2A-receptor actions
and impaired PFC function. Mutations of proteins such as the NE transporter
would lead to higher levels of NE in the synapse and excessive stimulation
of a1-receptors that would also
impair PFC function. It will be interesting to observe whether genetic
studies find associations between these proteins and ADHD symptoms, as
suggested by some preliminary studies. Genetic studies have already found
a consistent association between DA D4 receptor polymorphisms
and ADHD symptoms, particularly in adults. In this regard it is important
to remember that NE has very high affinity for D4 receptors;
indeed it has higher affinity for D4 than for noradrenergic
a- or b-receptors.
However, we do not currently understand how either DA or NE may act at
D4 receptors to alter PFC function.
The critical importance of NE to PFC
function may explain why selective noradrenergic agents have been successful
in treating ADHD. The nonselective a2-agonist,
clonidine, has had modest success in treating ADHD symptoms. More recently,
the selective a2A-agonist, guanfacine,
has also reduced symptoms of ADHD and improved performance of PFC tasks
in both open-label and controlled trials (reviewed in Arnsten, 2000).
Guanfacine likely reduces impulsivity and enhances attention regulation
by strengthening PFC control of behavior. Similarly, the nonselective
NE reuptake blocker, desipramine, and the new, selective NE reuptake blocker,
tomoxetine, have been shown to ameliorate ADHD symptoms. Noradrenergic
therapeutics will be the topic of the next column in this series.
The data presented here suggest possible
common mechanisms for how these compounds may be helpful in treating ADHD.
Both a2-agonists and NE reuptake
blockers may serve to normalize NE transmission in the PFC and thus enhance
PFC function. In subjects with underactivity of the NE system, these compounds
could increase postsynaptic a2-receptor
stimulation in the PFC through either direct stimulation of these receptors
(guanfacine) or by increasing available NE levels in the synapse (NE reuptake
inhibitors). Conversely, in subjects with overactivity of the NE system,
actions at presynaptic receptors might predominate to reduce NE tone.
However, it is important to remember that agents such as guanfacine can
improve PFC performance in normal subjects or in individuals with altered
DA activity. Thus, PFC cognitive enhancement with a2-agonists
does not necessarily signify altered NE activity. Instead, it is likely
that a variety of insults to PFC circuits can result in ADHD symptoms,
and enhanced noradrenergic a2-receptor
stimulation in PFC may help to overcome these problems irrespective of
their cause.
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