Elsevier

Biological Psychiatry

Volume 46, Issue 9, 1 November 1999, Pages 1234-1242
Biological Psychiatry

Norepinephrine: New Vistas for an Old Neurotransmitter
Attention-deficit/hyperactivity disorder (adhd) as a noradrenergic disorder

https://doi.org/10.1016/S0006-3223(99)00192-4Get rights and content

Abstract

This review revisits the thesis that a dysregulation of the central noradrenergic networks may underlie the pathophysiology of ADHD. We review the pertinent neurobiological and pharmacological literature on ADHD. The noradrenergic system has been intimately associated with the modulation of higher cortical functions including attention, alertness, vigilance and executive function. Noradrenergic activation is known to profoundly affect the performance of attention, especially the maintenance of arousal, a cognitive function known to be deficient in ADHD. Data from family, adoption, twin, and segregation analysis strongly support a genetic hypothesis for this disorder. Although molecular genetic studies of ADHD are relatively new and far from definitive, several replicated reports have found associations between ADHD with DAT and D4 receptor genes. Brain imaging studies fit well with the idea that dysfunction in fronto-subcortical pathways occurs in ADHD with its underlying dysregulation of noradrenergic function. A wealth of pharmacological data (within and without the stimulant literature) provides strong evidence for selective clinical activity in ADHD for drugs with noradrenergic and dopaminergic pharmacological profiles. Available research provides compelling theoretic, basic biologic and clinical support for the notion that ADHD is a brain disorder of likely genetic etiology with etiologic and pathophysiologic heterogeneity. Neurobiological and pharmacological data provide compelling support for a noradrenergic hypothesis of ADHD and suggest that drugs with noradrenergic activity may play an important role in the therapeutics of this disorder.

Introduction

A dysregulation of the central noradrenergic network has long been hypothesized to underlie the pathophysiology of ADHD Arnsten et al 1996, Pliszka et al 1996, Zametkin and Rapoport 1987. Although this hypothesis is largely derived from pharmacological data documenting that drugs showing efficacy in ADHD selectively modulate noradrenergic function, a noradrenergic hypothesis of ADHD is compelling in its own right. This is so considering that the noradrenergic system has been intimately associated with the modulation of higher cortical functions including attention, alertness, and vigilance. As recently reviewed by Solanto (1998), preclinical and clinical research has implicated the noradrenergic effects of stimulants as important therapeutic mechanisms on enhancing capacities such as delayed responding, working memory and attention. Furthermore, executive function and noradrenergic activation is known to profoundly affect the performance of attention, especially the maintenance of arousal, the ability to sustain attention on a subject, particularly a boring one. Moreover, attention and vigilance depend on adequate modulation by catecholamine neurotransmitters of prefrontal, cingulate and parietal cortices, thalamus, striatum, and hippocampus; brain networks with known high distribution of noradrenergic neurons.

Kornetsky’s landmark work in the 1970s first suggested a specific noradrenergic hypothesis of ADHD. After observing the behavioral effects of amphetamines, Kornetsky postulated that the hyperactivity in ADHD was caused by an increase in noradrenergic transmission (Kornetsky 1970). Consistent with this hypothesis, Zametkin proposed a decade later that ADHD may be associated with deficits in inhibitory frontostriatal connections that are predominantly driven by noradrenergic neurons on lower striatal structures that are predominantly driven by dopaminergic neurons (Zametkin and Rapoport 1987). Further support for a noradrenergic hypothesis of ADHD is documented in a recent comprehensive review of the role of catecholamines in ADHD by Pliszka et al (1996) that also suggests that the central noradrenergic system may be dysregulated in ADHD such that it does not efficiently prime the cortical posterior attention system to external stimuli. Concurrently with these ideas, Arnsten reviewed the literature in nonhuman primates demonstrating that norepinephrine in the prefrontal cortex enhances cognitive functioning through actions at alpha 2A adrenergic receptors postjunctional to noradrenergic terminals (Arnsten et al 1996). This neurobiological perspective fits very well with current neuropsychological, genetic, imaging and pharmacological data emerging in ADHD research that provides compelling support for a noradrenergic hypothesis of ADHD. Support for a critical role of noradrenergic functioning in higher cortical activity derives from basic research by Arnsten et al (1999) documenting that 1) adequate levels of noradrenaline (and dopamine) are necessary for optimal function of the prefrontal cortex; 2) that very high levels of catecholamine release (i.e., during severe stress) disrupt cognitive functions of the prefrontal cortex; and 3) that these alterations can improve with alpha2-adrenergic agonists (i.e., clonidine, guanfacine).

As recently reviewed by us (Faraone and Biederman 1998), ADHD is an early onset, heterogeneous disorder of inattention, hyperactivity and impulsivity. Its impact on society is enormous in terms of its financial cost, stress to families, adverse academic and vocational outcomes, and negative effects on self-esteem.

Family studies consistently support the assertion that ADHD runs in families Faraone and Biederman 1994a, Faraone and Biederman 1994b. Heritability data from twin studies of ADHD estimate the heritability of ADHD to be on average 0.80, indicating that genes play an important role in the etiology of this disorder. Adoption studies of ADHD also implicate genes in its etiology. The adoptive relatives of ADHD children are less likely to have ADHD or associated disorders than are the biological relatives of ADHD children Cantwell 1975, Morrison and Stewart 1973. Although the segregation analyses of ADHD suggest that a single gene is in the etiology of ADHD, the differences in fit between genetic models were modest, especially true for the comparison of multifactorial and single gene inheritance. This suggests that ADHD may be caused by several interacting genes of modest effect. This latter idea is consistent with ADHD’s high population prevalence and high concordance in monozygotic twins but modest recurrence risks to first degree relatives.

Molecular genetic studies of ADHD are relatively new and far from definitive. Hauser et al (1993) demonstrated that a rare familial form of ADHD was associated with mutations in the thyroid receptor-beta gene that causes generalized resistance to thyroid hormone (GRTH). One population-based association study implicated the A1 allele of the dopamine D2 receptor gene (Comings et al 1991), but no attempts to replicate this have been reported. Studies of the dopamine transporter (DAT) and D4 dopamine receptor (DRD4) genes have also been encouraging. Cook (1995) demonstrated an association between ADHD and the 480-bp allele of the dopamine transporter gene using a family-based association study. This finding was replicated in a population based study that found the 480-bp allele to be associated with ADHD, conduct disorder, Tourette’s symptoms and obsessions (Waldman et al 1996) and in a family based study by Gill et al (1997). These latter findings suggest, however, that the 480-bp allele may be a risk factor for several disorders. Using a “knockout” mouse model, Giros et al (1996) showed that disrupting the mouse DAT gene leads to a hyperdopaminergic phenotype that includes spontaneous hyperlocomotion. This may provide a simple animal model of hyperactivity and is consistent with the idea that abnormalities in the DAT gene could be a risk factor for ADHD.

Promising data have also emerged from studies of the dopamine D4 receptor (DRD4) gene. Ebstein et al (1996) reported a population study in which the 7-repeat allele of DRD4 was associated with novelty seeking. Persons high on this personality trait are impulsive, exploratory, excitable and quick-tempered, features that are seen among ADHD patients. The association between DRD4 and novelty seeking has been replicated in a study that combined both population and family based measures (Benjamin et al 1996) but not in another population study (Malhotra et al 1996). LaHoste et al (1996) noted several reasons why the DRD4 7-repeat allele has functional implications that are relevant for ADHD. This variant of DRD4 mediates a blunted response to dopamine. Moreover, the distribution of DRD4 mRNA in the brain suggests it plays a role in cognitive and emotional functioning. Thus, they completed a population study and found higher rates of the 7-repeat allele among ADHD children compared to control children carefully matched for ethnicity and gender. This result was maintained when the sample was increased by 50% (Sunohara et al 1997) and was also seen in a family-based association study of 52 families by the same group (Swanson et al 1998). Moreover, an ADHD-DRD4 family-based association was reported by Bailey et al (1997) and Faraone et al (1999) but was not found in a case-control study by Castellanos et al (1997). Despite these encouraging DRD4 data, it would be premature to consider DRD4 to simply be an ADHD gene because the positive association findings could be due to an unknown gene in linkage dysequilibrium with DRD4. Consistent with a noradrenergic hypothesis of ADHD, it is noteworthy that recent work has revealed that both epinephrine and noradrenaline act as potent agonists on the human dopamine D4 receptor (Lanau et al 1997).

Satterfield and Dawson (1971) were among the first to propose that ADHD symptoms were caused by fronto-limbic dysfunction. They suggested that weak frontal cortical inhibitory control over limbic functions might lead to ADHD. A review of the neurological literature (Mattes 1980) articulating the similarities between adult patients with frontal lobe damage and children with ADHD stimulated further research in this area.

Barkley (1997) has put forth a comprehensive unifying neuropsychological theory of ADHD that views the core deficit of ADHD, behavioral inhibition, as creating disturbances in five neuropsychological functions: working memory, internalization of speech, self-regulation of affect-motivation-arousal, behavioral analysis and synthesis, and motor control-fluency-syntax. Because of the complexity of frontal circuitry along with the limitations of neuropsychological inference, whether the “frontal” abnormalities in ADHD are due to “lesions” of frontal cortex or to brain areas with frontal projections is not yet clear. Thus, the term “fronto-subcortical,” which denotes a behavioral or cognitive dysfunction that looks “frontal” but may be influenced by subcortical projections, provides a suitable neuropsychological description of ADHD.

Because neuroimaging studies provide direct assessments of brain structure and function, they are ideal for testing hypotheses about the locus of brain dysfunction. There have been 16 controlled neuroimaging studies of ADHD children, adolescents and adults (see Faraone and Biederman 1998 for a detailed review and references). Ten of the eleven structural imaging studies, using either computerized tomography (CT) or magnetic resonance imaging (MRI) found some evidence of structural brain abnormalities among ADHD patients. Four of these studies found abnormalities in frontal cortex, usually limited to the right side, although the one structural study that examined adults reported no frontal abnormalities but did find sulcal widening, and cerebellar atrophy. Several other regions have been less consistently implicated. Among these, the finding of smaller volumes in subcortical structures is consistent with the idea that ADHD is a fronto-subcortical syndrome. There are 5 functional brain studies of ADHD, assessing either regional cerebral blood flow (rCBF) or glucose metabolism with positron emission tomography (PET). All of these find some evidence for brain dysfunction among ADHD patients, including adults and teenagers. Although the functional studies are consistent with the structural studies in implicating the fronto-subcortical system in the pathophysiology of ADHD, not all studies agree on the locus or lateralization of the observed impairments. Nevertheless, taken together, the brain imaging studies fit well with the idea that dysfunction in fronto-subcortical pathways occurs in ADHD and with its underlying dysregulation of noradrenergic function. Notably, the fronto-subcortical systems that control attention and motor behavior are rich in catecholamines, which have been implicated in ADHD by the mechanism of action of stimulants and other agents with documented activity in this disorder as described below.

Section snippets

The stimulants

Preclinical studies have shown that stimulants block the reuptake of dopamine and norepinephrine into the presynaptic neuron, and increase the release of these monoamines into the extraneuronal space. Early animal studies used 6-hydroxydopamine to lesion dopamine pathways in developing rats. Because these lesions created hyperactivity, they were thought to provide an animal model of ADHD. Although not entirely sufficient, changes in dopaminergic and noradrenergic function seem necessary for the

Summary

Current evidence support the notion that ADHD is a brain disorder of multiple causes: genes, biological substrates and psychosocial adversity. Moreover, the available data provide support for the etiologic and pathophysiologic heterogeneity of the disorder. The challenge for future research is to determine how susceptibility genes interact with the environment to cause ADHD. A clue to such an interaction has been provided by recent basic research by Arnsten et al (1999) that described an

Acknowledgements

This work was supported in part by grants R01MH41314 (Dr. Biederman) and R29MH57511 (Dr. Spencer) from the National Institutes of Health.

This work was presented at the conference, “Norepinephrine: New Vistas for an Old Neurotransmitter,” held in Key West, Florida in March 1999. The conference was sponsored by the Society of Biological Psychiatry through an unrestricted educational grant provided by Pharmacia & Upjohn. Abramowicz 1991, Luh et al 1995, Wilens et al 1996a, Wilens et al 1996b

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