Dopamine vs Noradrenaline: Inverted-U Effects and ADHD Theories

Abstract

The aim of the present study was to review the dopamine theory of attention-deficit–hyperactivity disorder (ADHD), in light of recent use of noradrenergic therapies. A historical review of pharmacological theories of ADHD was conducted, including inverted-U, spatial working memory and neural circuit aspects. Pharmacological advances, including animal and human studies of dopaminergic and noradrenergic mechanisms at the prefrontal cortex (PFC), indicate that α-2A adrenoreceptor stimulation results in increased dendritic firing during delay periods for preferred directions, while moderate levels of D1 receptor stimulation result in reduction of delay-related firing to non-preferred directions, allowing representational control in the PFC. Recent studies of the COMT val/met gene and stimulant medication response may help explain variation in inverted-U responses in individuals. Further studies utilizing delay-related firing paradigms should be useful in the investigation of attentional syndromes, and responses to newer pharmacological treatments.

Keywords

attention-deficit–hyperactivity disorder dopamine inverted-U noradrenaline working memory

Recent directions in the treatment of attention-deficit–hyperactivity disorder (ADHD) have involved a broadening of pharmacological perspectives to include noradrenergic as well as dopaminergic (DA) agents.

This offers an opportunity, in conjunction with animal studies, for a better understanding of the differential selectivity of these agents in the treatment of ADHD. A number of theories have been proposed for the effect of central nervous system stimulants on DA transmission in ADHD. Predominant theories in the 1980s were based on clinical studies showing improved behaviour on noradrenergic medications. Biederman et al. reported significant behavioural improvement on desipramine, but no Continuous Performance Test (CPT) changes [1]. Zametkin et al. reported improvement on the CPT for both MAO-A and MAO-B inhibiting agents, possibly suggesting both noradrenergic and DA effects [2].

Levy reviewed the dopamine theory of ADHD, based on both animal studies and pharmacological studies of the differential effects of stimulant medications [3]. Animal studies showed increased locomotor activity at low dexamphetamine doses and stereotypy at high doses [4, 5]. For example, Harris and Baldessarini showed that the dexamphetamine d-isomer was fourfold more potent than the l-isomer in striatal tissue, but only twofold more potent than l-amphetamine in inhibiting norepinephrine (NE) uptake, which could account for the fourfold difference of d- vs l-amphetamine, in inducing stereotypic behaviour in the rat, suggesting a DA effect [6].

Levy and Hobbes utilized the CPT to investigate the effect of a single pre-dose of haloperidol (0.04 mg kg⁻¹) on improvements in vigilance produced by methylphenidate (MPH) in 12 boys diagnosed with attention-deficit disorder with hyperactivity [7]. Haloperidol was shown to block the improvements on all the vigilance subtests, again suggesting a DA effect.

The important clinical issue of whether stimulant medications give rise to inverted-U effects with increased dose levels in ADHD children, has remained controversial since Sprague and Sleator reported that at low stimulant doses ADHD children showed a remarkable improvement on a short-term memory test at all levels of task load, whereas at higher doses there was a significant decrease in performance on the more difficult versions of the task [8]. In contrast, behaviour ratings continued to improve despite this cognitive decrement, up to a dose of 1.0 mg kg⁻¹. This was referred to as an inverted-U effect, and for a time it was influential in suggesting that low-dose regimens were optimal for ADHD children.

Grossberg described the inverted-U property, which enables a gated dipole circuit to maintain a golden mean in response to the circuit's arousal level [9]. The golden mean implies that circuit sensitivity to input fluctuations is optimal at moderate arousal levels, but degrades in different ways when the circuit is either under-aroused or over-aroused. For example, at low arousal, inputs must be larger than normal to overcome the dipole's increased response threshold, but once the threshold is overcome, the circuit is hyperexcitable above the threshold. The threshold can be brought into normal range by increasing its arousal until it reaches the peak of the inverted-U. Here the threshold is lower, but the network's excitability is also lower, because it generates small responses to inputs of arbitrary size.

A number of studies such as that of Evans and Pelham [10, 11], and Douglas et al. queried the Sprague and Sleator inverted-U result [8]. Douglas et al. reviewed the question of whether high doses of stimulants impaired flexible thinking in ADHD [11]. They reported a positive linear dose–response pattern on a number of cognitive tasks, based on the Wisconsin Card Sort, Trail-Making and Verbal Fluency tests, up to 0.9 mg kg⁻¹. Following these reports some clinicians used much higher dose ranges, sometimes well beyond 1.0 mg kg⁻¹ per day. But suspicions remained that subgroups of ADHD children might show adverse reactions to high-dose stimulants. For example, Solanto and Wender, and Tannock and Schachar reported the presence of subgroups within their samples who manifested adverse responses [12, 13]. Thus, the issue has continued largely unresolved. It may therefore be useful to re-examine the Sprague and Sleator findings and expand the question to implications for synaptic processes in the prefrontal cortex (PFC), which are involved in the maintenance of working memory, and theories of ADHD.

Prefrontal cortex working memory

Arnsten has discussed the fundamental work of Patricia Goldman-Rakic in investigating the role of PFC network activity, as a fundamental contribution to mind [14]. Goldman-Rakic defined working memory as ‘The ability to represent information no longer in the environment through recurrent excitation within a network of pyramidal cells with shared stimulus properties’ [15]. Brozoski et al. showed that dopamine was essential for spatial working memory operations of the PFC, and marked depletion of catecholamines from the dorsolateral PFC ‘was as devastating as removing the cortex itself’ [16]. Thus, although spatial working memory was used as a model system for examining functional circuitry, the principles were thought to apply to other sensory and affective domains described as ‘representational knowledge within parallel processing streams’.

Arnsten described the role of the PFC in working memory as applying representational knowledge to inhibit inappropriate action, thought and feelings, as well as inhibiting responses to distracting stimuli and suppressing irrelevant thoughts [17]. Arnsten equates these functions with executive function. She points out that stimulation of D1/D5 receptors in the PFC produces an inverted-U-shaped dose–response curve on working memory and attention regulation in the PFC, whereas high levels of dopamine release, which may occur during stress exposure, impair working memory and attention regulation. According to Arnsten, a similar inverted-U was described in monkeys performing a spatial working memory task, where moderate levels of D1/D5 receptor stimulation suppress delay-related firing for non-preferred spatial directions (i.e. noise) and thus enhance spatial tuning [17].

Goldman-Rakic proposed that the ability to guide behaviour by representation required mechanisms for selecting pertinent information, and for holding that information online for the temporal interval, over which a decision or operation is to be performed (i.e. working memory), and for executing motor commands [20]. Thus mechanisms are required for response initiation and inhibition (projections to striatum, tectum, thalamus and pre-motor cortex) as well as modulatory mechanisms (brainstem catecholamine projections). It was also proposed that connections between posterior parietal and prefrontal cortex are particularly relevant for the spatial–mnemonic processing of the type required in spatial delayed-response tasks or spatial working memory. Anatomical studies indicated a precise topographically organized network of connections between particular sectors of the parietal cortex and the principal pre-frontal sulcus. Parietal–prefrontal projections were described as reciprocated with prefrontal–parietal pathways, by feedforward and feedback pathways, representing a reverberating circuit for the short-term maintenance of the visuospatial representation needed in delayed response performance.

Arnsten and Goldman-Rakic were able to show that ‘many effects formerly attributed solely to DA, involved both NE and DA actions’ [21]. According to Arnsten both dopamine and noradrenaline exhibit an inverted-U dose/response, where either too little or too much impairs working memory [14]. For example, excessive D1 stimulation during stress was as detrimental to working memory as insufficient D1 receptor stimulation [22, 23]. In the case of NE Arnsten noted that levels of NE release in the PFC determine the type of adrenoreceptor engaged; that is, moderate levels of NE engage high-affinity α-2A receptors that couple to Gi and inhibit cAMP (response-element binding protein) signalling, whereas higher levels of NE, released during stress, engage lower affinity α-1 receptors, coupled to phosphotidyl inositol signalling, and lowest affinity β-1 receptors, to increase cAMP signalling [14]. Thus PFC working memory function is improved by NE α-2A receptor stimulation, but impaired by high levels of D1 and by α-1 and β-1 receptor stimulation.

Arnsten has suggested that both dopamine and noradrenaline effects on cell firing are related to arousal [14]. Thus phasic firing of DA neurons is thought to be related to expectation of reward [24], while stress may induce high tonic DA levels. According to Arnsten, phasic NE levels are related to levels of interest, while tonic levels are silent during sleep and increase from alertness to high levels when stressed. She noted that while moderate levels engage the α-2A receptor, higher levels released during stress engage lower affinity α-1 receptors, and β-1 receptors. The PFC working memory function is improved by α-2A receptor levels and moderate levels of DAD1 receptor stimulation, but is impaired by high levels of D1 and α-1 and β-1 receptor stimulation, which promote affective and sensorimotor amygdala and posterior cortical functions.

Finally, an important distinction outlined by Arnsten relates to the location of D1 and α-2A signalling mechanisms on dendritic spines [14]. She noted that under optimal neurochemical conditions, moderate levels of NE engage α-2A receptors, and increase signals, whereas moderate levels of DAD1 receptor stimulation decrease ‘noise’. These beneficial effects of α-2A versus DAD1 arise from opposing effects on cAMP signalling, where α-2A stimulation inhibits [25], while DAD1 activates cAMP production [19]. cAMP is thought to increase the probability of hyperpolarization-activated cyclic nucleotide-gated cation channels (HCN channels) opening in response to changes in membrane potential. Interestingly, α-2A adrenoreceptor stimulation is thought to result in closure of HCN channels on spines receiving inputs from neurons with similar spatial properties, thus increasing firing during delay periods for preferred directions, while moderate levels of D1 receptor stimulation lead to opening of HCN channels on spines receiving inputs from neurons with dissimilar spatial properties, reducing delay-related firing to non-preferred directions.

Acute stress reactions

Arnsten also discussed the ‘collapse of PFC networks during stress’ [14]. This is thought to occur when excessive cAMP firing opens HCN channels throughout distal dendrites, disconnecting all cortical–cortical connections, thus disabling delay-related firing in the PFC. Arnsten points out that ADHD and post-traumatic stress disorder (PTSD) are common conditions that involve prominent PFC dysfunction, and both appear to involve catecholamine changes in the extracellular compartment. While ADHD is thought to be associated with insufficient catecholamine stimulation, PTSD is associated with excessive NE release. Thus effective treatments for ADHD all act to increase catecholamine transmission.

According to Arnsten ADHD is linked to genetic changes that reduce catecholamine transmission to suboptimal levels, and is treated with agents that increase catecholamine transmission, whereas PTSD is associated with amplified noradrenergic transmission that impairs PFC, but strengthens amygdala function, and is treated with agents that block α-₁ or β-adrenoreceptors [14].

Thus a better understanding of synaptic transmission and neural circuit function in the PFC is important in resolving longstanding questions in relation to noradrenergic versus DA functions in ADHD. An understanding of inverted-U functions is also important in suggesting that relatively low-dose medication regimens may be advisable for optimal PFC functioning in ADHD children. A rider to this conclusion, however, may relate to baseline catecholamine levels, giving rise to the individual variation observed in clinical populations.

Neural circuits

Neuroimaging studies have directed attention to morphological and physiological differences in right-sided, prefrontal–striatal systems, which are rich in DA innervation [26–28].

Dopamine is thought to exert a modulating influence on the dlPFC. It is believed that prefrontal pyramidal neurons may directly excite mesocortical DA neurons in the ventral mesencephalon and indirectly inhibit mesostriatal DA cells through activation of GABAergic neurons in mesencephalic cell nuclei [29]. Thus reduction in PFC cell activity leads to an excess of DA receptor activation at subcortical nuclei. In the primate dlPFC, D1 receptors are the most abundant DA receptor subtype, and mediate most of the cellular effects of DA in this subtype, and mediate most of the cellular effects of DA in this region [30]. Thus D1 receptors regulate sustained firing of dlPFC neurons during the delay phase of delayed-response tasks that require working memory [31, 32]. DA neurons may also have an important role in gating information loaded into working memory buffers [33–35].

Castellanos, and Swanson and Castellanos proposed that presynaptic effects may predominate in D2-rich subcortical regions, where presynaptic receptors are abundant, producing decreased synaptic dopamine, while post-synaptic effects may predominate in D4-rich cortical regions, which lack presynaptic receptors, producing increased synaptic dopamine [36, 37]. Castellanos [36] suggested a model whereby dopamine neurons originating in the ventral tegmental area diffusely innervate the frontal cortex, forming the mesocortical dopamine system, which largely lacks inhibitory autoreceptors. He suggested that these DA terminals were ideally positioned to regulate cortical inputs, thus improving signal-to-noise ratio for biologically valuable signals. In contrast, symptoms of hyperactivity/impulsivity in children with ADHD were hypothesized to be associated with relative overactivity of the nigral–striatal circuit, which is tightly regulated by inhibitory autoreceptors, as well as by long-distance feedback from the cortex. These differences were thought to explain differential dose–response effects of stimulant medications, where low doses acting at the striatal level might produce therapeutic inhibition of DA neurotransmission, while non-therapeutic high doses, especially if delivered i.v. or intra-nasally might overwhelm this inhibitory effect.

Frank et al. proposed a neurocomputational model, which includes both frontostriatal DA and noradrenaline functions, to explain cognitive and motivational deficits in ADHD [38]. They suggested that ADHD is not a unitary disorder. Sonuga-Barke and Castellanos et al. proposed a dual-pathway model, implicating separate corticostriatal circuits in motivational and executive dysfunction in ADHD [39, 40]. Response inhibition deficits were proposed to reflect damage to prefrontal–dorsal striatal circuits, whereas motivational and reward deficits stem from dysfunction in ventral striatal–orbitofrontal circuits.

Frank et al. noted that their model has important similarities and differences with that of Castellanos et al. [38, 40]. Both models postulate core motivational deficits in ADHD. The Frank et al. model postulated that low striatal DA levels in ADHD lead to deficits in ‘Go’ learning from positive reinforcement, which are alleviated by stimulant medications. They also suggested, based on reaction time variability and erratic trial-to-trial switching on an AX-Continuous Performance Task, that these variables were not accounted for by DA mechanisms, but rather by cortical noradrenergic dysfunction. The model also predicted a specific impairment in gating (rather than maintenance per se) of working memory representations, and that basal ganglia gating signals were necessary to update only task-relevant information, and to gate distracting information.

According to Lewis and Gonzalez-Burgos, dendritic spines are the principal targets of excitatory synapses to pyramidal neurons [29]. Excitatory connections from the mediodorsal thalamus, the principal source of inputs to the dlPFC, synapse primarily on dendritic spines. Dendritic spine density on dlFPC layer 3 pyramidal neurons undergoes a substantial decline during adolescence in primates. Activity-dependent strengthening and pruning appears to underlie synapse stabilization. It is suggested that functionally immature synapses may not be able to provide compensation for synaptic dysfunction prior to adolescence, because they have a very low A-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA; post-synaptic receptor for glutamate) receptor contribution, rendering them silent at the resting memory potential, and a relatively high probability of glutamate release. They are thus subject to quick exhaustion of glutamate pools after repetitive activation. It is likely that a range of factors including labour, delivery, alcohol, nicotine and other stressors may affect the development of dlPFC circuitry.

The work of Arnsten has clarified the role of α₂-noradrenergic mechanisms in ADHD [41]. Reciprocal connections were hypothesized between the PFC and locus caeruleus. Previous studies had focused on the significance of DA input to the PFC, but research in monkeys indicated beneficial effects of α₂ NE agonists on delayed-response performance in aged monkeys. As distinct from α-2B and α-2C agonists that have sedative and hypotensive actions, guanfacine, which is a more specific α-2A agonist, was shown to enhance cognitive performance in monkeys.

Arnsten et al. have described research in rodents and primates that indicates that noradrenaline has an important influence on spatial working memory and attentional functions of the PFC [42]. They have shown beneficial effects of guanfacine on cognitive tasks, such as delayed response, delayed alternation and delayed match to sample with repeated stimuli, and believe that these effects are mediated via the post-synaptic α-2A receptor. Arnsten et al. proposed that post-synaptic α-2A receptor stimulation inhibits irrelevant and distracting sensory processing through effects on pyramidal cells that project to sensory association cortices. This suggested that guanfacine, an α-2A agonist, may be of benefit to ADHD children, and suggests an adrenergic role in working memory, as discussed here. Interestingly, Arnsten et al. noted that in the case of ADHD, therapeutic low doses of stimulants are found to have a greater effect on NE than DA [43–45].

Noradrenergic medications

Arnsten et al. have described three different subtypes of α-2 adrenoreceptors in humans, the α-2A α-2B and α-2C subtypes [46]. The α-2A and α-2C subtypes are widely distributed in the brain, including the PFC; the α-2B receptor is most concentrated in the thalamus. Guanfacine is thought to be the most selective agonist available for the α-2A subtype. In contrast, the sedating effects of clonidine are thought to involve the thalamus, basal forebrain and other α-2B and α-2C effects. Atomoxetine, which also has sedating effects in some children, may also have α-2B and/or α-2C effects [46].

A recent randomized, double-blind, placebo-controlled study of guanfacine extended release in ADHD children aged 6–17 years showed significant improvement in hyperactivity/impulsivity and inattentiveness on a number of parent and teacher rating scales [47]. In contrast, clonidine has been recommended mainly for augmentation of stimulant effects [48].

Working memory

The role of working memory in ADHD is also controversial [49]. This may relate to a number of factors including age or development, and also measurement methods used to assess working memory. Martinussen et al. carried out a meta-analysis of 26 empirical research studies of working memory impairments in children with ADHD, published from 1997 to December 2003, and reported that overall effect sizes for spatial storage and spatial central executive were greater than those obtained for verbal storage and verbal central executive. The authors concluded that the evidence supported theoretical models implicating working memory processes in ADHD. Nigg reported a meta-analysis of neuropsychological measures in normal and ADHD children [50]. He found that spatial working memory had the largest performance differences in ADHD children, and suggested that medication reverses these deficits.

Kerns et al. reported a study in which 21 children with ADHD (aged 6–13 years) were compared with matched controls on measures of working memory, behavioural inhibition, attention, and time reproduction [51]. They found that children with ADHD performed significantly worse than controls on measures of inhibition, attention, and time reproduction, but did not differ significantly from controls on working memory tasks. Barnett et al. sought to examine factors associated with spatial working memory, and impairments in medicated, non-medicated children with ADHD, and controls [52]. They utilized a computerized Spatial Working Memory Task, in which subjects were required to search through boxes appearing on a screen, with the aim of finding blue tokens hidden inside. The results showed that medication-naïve ADHD children performed significantly worse, while there was no difference between medicated children with ADHD, and controls. The investigators concluded that the deficit in spatial working memory in children with ADHD was characterized by an inability to hold multiple pieces of spatial information concurrently in memory. This difference, however, was manifest only when the task was more difficult, in terms of six- and eight-box trials.

Genetic implications

Genetic studies have suggested associations of ADHD with both the dopamine transporter DAT, [53, 54] and dopamine DRD4 receptor 7-repeat allele [55–57]. While there have been a number of reviews of putative genes associated with ADHD [53–59] there have been fewer studies or reviews of the separate question of genes associated with response to stimulant medications [60–62]. The Swanson et al. review suggested that DRD4 and DAT gene polymorphisms have selective additive adverse effects on IQ in ADHD subjects, which could be reflected in working memory [60].

Cheon et al. [62] reported an association between the COMT valine (Val) 108/158 methionine (Met) polymorphism and the response to treatment with MPH in children with ADHD. The authors studied 124 children with ADHD, who had an improvement ≥50% after 8 weeks of treatment with MPH. They also found that 62.5% of the patients having a good response to MPH treatment had the Val/Val genotype, while 41.7% and 11.7%, respectively, of patients having a poor response had the val/met genotype and met/met genotypes. This is one of the first studies to show clear genetically determined dose–response effects in children, and suggests that individual variations in stimulant dose–response levels are subject to an inverted-U response, as suggested by Sprague and Sleator [8], but that the level of the inverted-U is likely determined by genotype. It should be pointed out that response to a medication is not necessarily the same as aetiology. This is particularly so in ADHD, in which aetiology and physiology may be determined by complex genetic and developmental factors, while treatment response could reflect genetically determined effects on PFC, and related subcortical centres.

Conclusion

It is important to distinguish genetic and other factors important for medication response from aetiological factors that may or may not determine response to medication. The understanding of the genetics of inverted-U effects may help to predict those variations in stimulant dose–response behaviour in ADHD, which have continued to give rise to controversy, since Sprague and Sleator [8]. Thus variation in the COMT val/met polymorphism should theoretically alter the golden mean dose level, at which a positive response in one individual determines a negative response in another.

The findings that α-2A adrenoreceptor stimulation is thought to result in increased firing during delay periods for preferred directions, while moderate levels of D1 receptor stimulation result in reduction of delay-related firing to non-preferred directions, provides a basic mechanism for maintenance of representational control. The investigations of delay-related firing by Arnsten [14], based on the pioneering work of Patricia Goldman-Rakic, have pointed to a fundamental aspect of behaviour control, which can be impaired in a number of psychiatric syndromes, while further studies utilizing delay-related firing paradigms, such as the Continuous Performance Test and Delayed Matching to Sample Task, should be useful in the investigation of attentional syndromes, and responses to newer pharmacological treatments.

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